Nociceptive neuron specific calcium channel isoform and uses thereof

ABSTRACT

The invention pertains to N-type calcium channel isoforms containing exon 37a (Cav2.2e[37a]), which are specifically expressed in nociceptive neurons, and nucleic acids relating thereto. Also included are methods for identifying antagonists of Cav2.2e[37a] subunit activity that act by inhibiting the expression or function of the subunit. The invention further relates to methods of using such nucleic acids, polypeptides, and inhibitor molecules in the treatment and/or diagnosis of disease, such as in methods for treating pain, particularly neuropathic pain.

RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 19(e) of U.S. provisional application serial No. 60/443,474, filed Jan. 29, 2003, the disclosure of which is incorporated by reference herein.

GOVERNMENT SUPPORT

[0002] This work was funded in part by the National Institutes of Health under grant numbers NS29967 and NS43082. The government may have certain rights in this invention.

FIELD OF THE INVENTION

[0003] The invention pertains to N-type calcium channel subunit isoforms that are preferentially expressed in nociceptive neurons.

BACKGROUND OF THE INVENTION

[0004] Nociceptive neurons in the dorsal root ganglia (DRG) respond to a wide variety of stimuli including heat, protons, and capsaicin (McCleskey and Gold, 1999). Nociceptive neurons have been identified based on a number of criteria including morphological, biophysical, and molecular properties. Capsaicin-responsiveness has been used as an important functional indicator of a sub-set of nociceptors that are also heat sensitive (Caterina and Julius, 2001; McCleskey and Gold, 1999).

[0005] Voltage gated calcium channels, also known as voltage dependent calcium channels, are multisubunit membrane spanning proteins which permit controlled calcium influx from an extracellular environment into the interior of a cell. Several types of voltage gated calcium channel have been described in different tissues, including N-type, P/Q-type, L-type and T-type channels. A voltage gated calcium channel permits entry into the cell of calcium upon depolarization of the membrane of the cell, which is a lessening of the difference in electrical potential between the outside and the inside of the cell.

[0006] Voltage-gated calcium (Ca) channels expressed in nociceptive neurons are present at presynaptic nerve terminals in the dorsal horn of the spinal cord where they regulate transmitter release. Consistent with this, the selective inhibitor of the N-type calcium channel, MVIIA which is also called SNX 111 or ziconotide, is a powerful analgesic (Bowersox et al., 1996; Brose et al., 1997; Chaplan et al., 1994; Cox, 2000). Further, mice lacking the N-type Ca_(V)2.2 subunit have higher pain thresholds compared to wild type (Hatakeyama et al., 2001; Kim et al., 2001; Saegusa et al., 2001; Saegusa et al., 2002). The N-type channel is also present at numerous other synapses and its importance in maintaining sympathetic tone is a major complication in analgesic therapy with N-type channel blockers (Ino et al., 2001; Miljanich and Ramachandran, 1995; Vanegas and Schaible, 2000). Consequently, there is considerable interest in establishing whether nociceptive neurons express a unique class of N-type channel. This possibility has gained momentum with growing appreciation that the Ca_(V)2.2 gene, which encodes the functional core of the N-type Ca channel, is subject to extensive alternative splicing that in some cases is tissue-specific (Lipscombe et al., 2002).

[0007] Previous studies have compared calcium currents in nociceptive and non-nociceptive neurons distinguished on the basis of various criteria (Blair and Bean, 2002; Cardenas et al., 1995; Petruska et al., 2000; Regan et al., 1991; Scroggs and Fox, 1992a). The most consistent difference reported is the presence of a larger low threshold T-type calcium current in normociceptive compared to nociceptive neurons. Recent studies suggest that the Ca_(V)3.2 T-type channel localizes to mechanoreceptors (Shin et al., 2003). Differences in high threshold, N-type currents of nociceptive compared to non-nociceptive neurons have not been reported.

[0008] Molecular analyses of RNA isolated from dorsal root ganglia have, nonetheless, provided evidence for the presence of multiple splice forms of the N-type Ca_(V)2.2 subunit that differ in their intracellular domains, and S3-S4 extracellular linkers (Lin et al., 1997; Lin et al., 1999; Lu and Dunlap, 1999; Pan and Lipscombe, 2000). None of the splice forms of Ca_(V)2.2 identified to date are exclusively expressed in dorsal root ganglia (Lipscombe et al., 2002).

[0009] Therefore, there is a need for the identification of splice isoforms of N-type calcium channel subunits that are preferentially or specifically expressed in nociceptive neurons. Identification of such differential expression of isoforms would permit the development of therapeutics which are specific for the distinct isoforms, thereby lessening side effects resulting from the use of therapeutics which are effective for more than one calcium channel isoform.

SUMMARY OF THE INVENTION

[0010] Based upon RT-PCR expression analysis, functional screening for capsaicin-responsiveness, and biophysical analysis at the single cell level, we present herein the identification of a novel splice isoform of the Ca_(V)2.2α subunit of N-type calcium channels, which is preferentially expressed in a sub-set of nociceptive neurons, and which contains exon 37a. The subunit is referred to herein as “Ca_(V)2.2e[37a]”. The presence of exon 37a in Ca_(V)2.2 correlates with significantly larger N-type currents in neurons and non-neuronal expression systems.

[0011] We report the preferential expression of a splice variant of the Ca_(V)2.2 calcium channel in neurons sensitive to capsaicin. Given that distribution, it is clear that a screening assay for compounds that would preferentially block pain receptors can be established by comparing the compounds' activity on the Ca_(V)2.2 exon 37a variant and the Ca_(V)2.2 exon 37b variant, the latter being the control. Most ideally, the screening would be carried out in vitro on neurons genetically engineered to express either the 37a or 37b variant and acrivity of the compounds would be measured as a reduction in calcium current.

[0012] The invention provides isolated nucleic acid molecules that encode Ca_(V)2.2e[37a], fragments of those molecules, expression vectors containing the foregoing, and isolated host cells transfected with those molecules. The invention also provides isolated Ca_(V)2.2e[37a] polypeptides and fragments thereof, as well as inhibitors of the foregoing nucleic acids and polypeptides which modulate voltage-gated calcium influx. The foregoing can be used in the diagnosis or treatment of conditions characterized by increased or decreased N-type calcium channel activity correlated with the presence of the Ca_(V)2.2e[37a] subunit and can be used in methods to identify molecules that are therapeutically useful to modulate N-type calcium activity correlated with the presence of the Ca_(V)2.2e[37a] subunit, most particularly for treatment of pain (e.g., neuropathic pain), by modulating voltage regulated calcium influx.

[0013] The invention involves in one aspect recombinantly expressed Ca_(V)2.2 nucleic acids and polypeptides which include exon 37 a or the amino acid sequence encoded thereby (CCRIHYKDMYSLLRCIAPPVGLGKNCPRRLAYK, SEQ ID NO:45). The first amino acid (Cys) in the amino acid sequence set forth as SEQ ID NO:45 is partly encoded by the end of exon 36 and partly encoded by beginning of exon 37a, as the reading frame is not aligned to the exon-exon junctions. The amino acid sequence set forth as SEQ ID NO:45 is identical in human, mouse and rat. The nucleotide sequence that encodes SEQ ID NO:45 is identical in human and rat, but not in mouse (which therefore has a degenerate nucleotide sequence).

[0014] In one embodiment, the polypeptide comprises the amino acid sequence of SEQ ID NO:45, and preferably consists of the amino acid sequence of SEQ ID NO:45. In another embodiment the Ca_(V)2.2 polypeptide is a fragment or variant of the foregoing polypeptides, wherein the fragment or variant includes additions, deletions or substitutions of the amino acid sequence of SEQ ID NO:45 which confer the same function as SEQ ID NO:45. Preferred variants include those having additions, substitutions or deletions relative to the Ca_(V)2.2e[37a] polypeptide sequence disclosed herein, particularly those variants which retain one or more of the activities of the Ca_(V)2.2e[37a], including subunits with various other splice variations.

[0015] According to another aspect of the invention, isolated cells that recombinantly express an N-type calcium channel comprising a Ca_(V)2.2 subunit that comprises exon e37a (Ca_(V)2.2e[37a]) are provided. In some embodiments, the Ca_(V)2.2e[37a] subunit has a human sequence, a mouse sequence or a rat sequence. In preferred embodiments, the cell is a neuron or an oocyte.

[0016] According to still another aspect of the invention, isolated neurons that express an N-type calcium channel comprising a Ca_(V)2.2 subunit that comprises exon e37a (Ca_(V)2.2e[37a]) are provided. In some embodiments, the neuron further expresses a marker of nociceptive neurons. Preferably the marker of nociceptive neurons is Na_(V)1.8 or vanilloid receptor VR1. In particularly preferred embodiments, the neuron expresses both Na_(V)1.8 and vanilloid receptor VR1.

[0017] In another aspect of the invention, methods are provided for identifying lead compounds for a pharmacological agent useful in the treatment of disease associated with increased or decreased voltage regulated calcium influx mediated by a N-type calcium channel containing a Ca_(V)2.2e[37a] subunit. The methods include providing a cell or other membrane-encapsulated space comprising a Ca_(V)2.2e[37a] polypeptide; contacting the cell or other membrane-encapsulated space with a candidate pharmacological agent under conditions which, in the absence of the candidate pharmacological agent, cause a first amount of voltage regulated calcium influx into the cell or other membrane-encapsulated space; and determining a test amount of voltage regulated calcium influx as a measure of the effect of the lead compounds for a pharmacological agent on the voltage regulated calcium influx mediated by a N-type calcium channel containing a Ca_(V)2.2e[37a] subunit. A test amount of voltage regulated calcium influx which is less than the first amount indicates that the candidate pharmacological agent is a lead compound for a pharmacological agent which reduces voltage regulated calcium influx. A test amount of voltage regulated calcium influx which is greater than the first amount indicates that the candidate pharmacological agent is a lead compound for a pharmacological agent which increases voltage regulated calcium influx. In some embodiments, the methods also include a step of loading the cell or other membrane-encapsulated space with a calcium-sensitive compound which is detectable in the presence of calcium, wherein the calcium-sensitive compound is detected as a measure of the voltage regulated calcium influx.

[0018] In a preferred embodiment, the pharmacological agent that specifically reduces voltage regulated calcium influx mediated by a N-type calcium channel containing a Ca_(V)2.2e[37a] subunit is an agent that reduces N-type calcium channel current densities in nociceptive neurons. In another preferred embodiment, the pharmacological agent that specifically reduces voltage regulated calcium influx mediated by a N-type calcium channel containing a Ca_(V)2.2e[37a] subunit is useful as an analgesic agent.

[0019] Methods for identifying compounds which selectively or preferentially bind a N-type calcium channel containing a Ca_(V)2.2e[37a] subunit also are provided in another aspect of the invention. The methods include providing a first cell or membrane encapsulated space which expresses a N-type calcium channel that contains a Ca_(V)2.2e[37a] subunit, providing a second cell or membrane encapsulated space which expresses a N-type calcium channel that does not contain a Ca_(V)2.2e[37a] subunit, wherein the second cell or membrane encapsulated space is identical to the first cell except for the N-type calcium channel expressed, contacting the first cell or membrane encapsulated space and the second cell or membrane encapsulated space with a compound, and determining the binding of the compound to the first cell or membrane encapsulated space and the second cell or membrane encapsulated space. A compound which binds the first cell or membrane encapsulated space but does not bind the second cell or membrane encapsulated space is a compound which selectively binds the N-type calcium channel that contains a Ca_(V)2.2e[37a] subunit. A compound which binds the first cell or membrane encapsulated space in an amount greater than the compound binds the second cell or membrane encapsulated space is a compound which preferentially binds the N-type calcium channel that contains a Ca_(V)2.2e[37a] subunit. In a preferred embodiment, the N-type calcium channel that does not contain a Ca_(V)2.2e[37a] subunit is a N-type calcium channel that contains a Ca_(V)2.2e[37b] subunit.

[0020] In a further aspect of the invention, methods for identifying compounds which selectively or preferentially bind to a Ca_(V)2.2e[37a] isoform are provided. The methods include providing a Ca_(V)2.2e[37a] isoform polypeptide or nucleic acid, providing a Ca_(V)2.2e[37b] isoform polypeptide or nucleic acid, contacting the Ca_(V)2.2e[37a] isoform polypeptide or nucleic acid and the Ca_(V)2.2e[37b] subunit isoform polypeptide or nucleic acid with a compound, and determining the binding of the compound to the Ca_(V)2.2e[37a] isoform polypeptide or nucleic acid and the Ca_(V)2.2e[37b] isoform polypeptide or nucleic acid. A compound which binds the Ca_(V)2.2e[37a] isoform polypeptide or nucleic acid but does not bind the human N-type calcium channel Ca_(V)2.2e[37b] isoform polypeptide or nucleic acid is a compound which selectively binds the Ca_(V)2.2e[37a] isoform, and wherein a compound which binds the Ca_(V)2.2e[37a] isoform polypeptide or nucleic acid in an amount greater than the compound binds the Ca_(V)2.2e[37b] isoform polypeptide or nucleic acid is a compound which preferentially binds the Ca_(V)2.2e[37a] isoform.

[0021] In the foregoing methods for identifying compounds which selectively or preferentially bind to a Ca_(V)2.2e[37a] isoform, the compound preferably is an antibody or a antigen-binding fragment thereof, a nucleic acid molecule or one or more compounds from a library of molecules. Preferably the library is a natural product library or a library generated by combinatorial chemistry.

[0022] According to yet another aspect of the invention, methods for preparing an analgesic agent are provided. The methods include identifying an agent that selectively or preferentially reduces calcium channel current densities in nociceptive neurons mediated by N-type calcium channels containing a Ca_(V)2.2e[37a] subunit, and formulating the agent for administration to a subject in need of such treatment. The methods also can include identifying a compound according to the foregoing methods, and formulating the compound for administration to a subject in need of such treatment.

[0023] In another aspect, the invention provides double stranded RNA molecules specific for Ca_(V)2.2e[37a] RNA. Preferably the double stranded RNA molecule is a siRNA molecule useful in RNA interference. Preferred embodiments include double stranded RNA molecules that are 21-23 nucleotides in length and/or that have a 3′ overhang. Preferably the 3′ overhang is 2 nucleotides in length. In still other embodiments, the double stranded RNA molecule is a single molecule that comprises a hairpin structure.

[0024] In a further aspect of the invention, methods for inhibiting calcium influx in a neuronal cell mediated by a N-type calcium channel containing a Ca_(V)2.2e[37a] subunit are provided. The methods include contacting the neuronal cell with an amount of a Ca_(V)2.2e[37a] inhibitor effective to inhibit calcium influx in the mammalian cell. In some embodiments, the inhibitor is selected from the group consisting of an antibody which selectively binds the Ca_(V)2.2e[37a] polypeptide, an antisense nucleic acid that reduces expression of a Ca_(V)2.2e[37a] polypeptide, a siRNA that reduces expression of a Ca_(V)2.2e[37a] polypeptide.

[0025] According to another aspect of the invention, methods for treating a subject afflicted by pain mediated by a N-type calcium channel containing a Ca_(V)2.2e[37a] subunit are provided. The methods include administering to a subject in need of such treatment an inhibitor of the Ca_(V)2.2e[37a] polypeptide in an amount effective to inhibit voltage regulated calcium influx and thereby to reduce the pain. In some embodiments, the inhibitor is selected from the group consisting of an antibody which selectively binds the Ca_(V)2.2e[37a] polypeptide, an antisense nucleic acid that reduces expression of a Ca_(V)2.2e[37a] polypeptide, a siRNA that reduces expression of a Ca_(V)2.2e[37a] polypeptide.

[0026] In the foregoing methods, the inhibitor is administered prophylactically to a subject at risk of being afflicted with pain. Preferably the pain is neuropathic pain.

[0027] Use of the foregoing compositions in the preparation of a medicament, and particularly in the preparation of a medicament for the treatment of stroke, pain (e.g., neuropathic pain), traumatic brain injury, or a condition which results from excessive or insufficient voltage regulated calcium influx, is provided.

[0028] These and other aspects of the invention are described in greater detail below.

BRIEF DESCRIPTION OF THE FIGURES

[0029]FIG. 1 shows RT-PCR analysis of e37a and e37b splice variants.

[0030]FIG. 2 shows RT-PCR analysis of e37a and e37b in single DRG neurons.

[0031]FIG. 3 shows single cell RT-PCR (scRT-PCR) analysis of Ca_(V)2.2 e37a and e37b in capsaicin-responsive and capsaicin-non-responsive neurons.

[0032]FIG. 4 shows the experimental protocol used in various experiments.

[0033]FIG. 5 shows whole cell calcium currents in capsaicin-responsive and capsaicin-non-responsive neurons.

[0034]FIG. 6 shows that ω-Ctx GVIA-sensitive calcium currents in capsaicin-responsive and capsaicin-non-responsive neurons.

[0035]FIG. 7 shows that LVA currents rundown significantly over a 5 minute time period in capsaicin-non-responsive neurons.

[0036]FIG. 8 shows ω-Ctx GVIA-sensitive calcium currents in capsaicin-responsive neurons that contain and lack e37a.

[0037]FIG. 9 shows competitive RT-PCR analysis of e37a and e37b in whole tissue and single neurons.

[0038]FIG. 10 shows that multiple splice forms of Ca_(V)2.2 are expressed in dorsal root ganglia. FIG. 10a, Putative membrane topology of the Ca_(V)2.2 subunit. The approximate location of constitutively expressed exons (horizontal black lines) and alternatively spliced exons, e18a, e24a, e31a and e37a/e37b (blue circles) are shown. FIG. 10b, RT-PCR analysis of e18a, e24a, and e31a in mRNA isolated from rat DRG. Primers flanked each splice site and generated the following products: 227 and 290 bp for Δe18a and +e18a; 114 and 126 bp for Δe24a and +e24a; and 169 and 175 bp for Δe31 a and +e31 a. PCR-derived cDNA products were separated on a 2% agarose (e18a) or 4% Metaphor agarose gel (e24a and e31a). Results are consistent with previous analyses of these sites of alternative splicing by RT-PCR and ribonuclease protection assays (Lin et al., 1997; Lin et al., 1999; Pan and Lipscombe, 2000).

[0039]FIG. 11 shows that capsaicin-responsiveness in DRG neurons is correlated with the presence of VR1. DRG neurons were screened for capsaicin-responsiveness by whole cell recording (n=269 cells). Whole cell currents recorded from FIG. 11a, a non-responsive neuron and FIG. 11b, a capsaicin-responsive neuron. The membrane potential was voltageclamped at −60 mV. The horizontal bar indicates the time and duration of capsaicin application (2 μM). No inward current was detected in 141 neurons. Inward currents were induced in 128 neurons during capsaicin challenge, with an average amplitude of 986±118 pA. FIG. 1c, PCR-derived cDNA products amplified in two sets of reactions from 5 individual neurons (lanes 1-5) using VR1 and GAPDH-specific primers. The predicted size of PCR products was 125 bp and 274 bp, respectively. The capsaicin-responsiveness of each cell is indicated between gels (+ or −). FIG. 1d, Histogram showing the percentage of non-responsive cells (gray) and capsaicin-responsive cells (red) containing VR1. PCR products were amplified in 89% of capsaicin-responsive cells (25 of 28) with VR1 primers compared to 13% of non-responsive cells (2 of 15).

[0040]FIG. 12 shows that expression patterns of exons, e18a, e24a, and e31a, do not correlate with capsaicin-responsiveness. Representative gels showing single cell RT-PCR-derived cDNA products amplified using Ca_(V)2.2-specific primers flanking exons FIG. 12a, eb18a; FIG. 3b, e24a; and FIG. 12c, e31a, together with histograms summarizing the distribution of exons based on capsaicin-responsiveness. Control GAPDH-specific primers are used in each single cell reaction. Products amplified from four cells are shown for each primer pair (lanes 1-4). In FIG. 12c, the first two lanes show products amplified from Ca_(V)2.2e[Δ31a] and Ca_(V)2.2e[+e31 a] clones to establish that a 6 bp difference is resolvable in a 4% Metaphor gel. Sizes of cDNA products were respectively, 227 bp and 290 bp for Δe18 and +e18a; 114 bp and 126 for Δe24a and +e24a; and 169 bp and 175 bp for .e31a and +e31a. Histograms show percent cells that lack the specified exon (A) and that express both splice isoforms lacking and containing the exon (both). Histograms separate cells based on capsaicin-non-responsiveness (gray) and capsaicin-responsiveness (red). The total number of cells analyzed is shown below each histogram. Capsaicin responsiveness of each cell is indicated between gels (+ or −).

[0041]FIG. 13 shows that exon 37a is expressed exclusively in dorsal root ganglia. FIG. 13a, Splicing pattern of mutually exclusive exons e37b and e37a of Ca_(V)2.2e[37a] based on analysis of the public rat genomic sequence (accession number NW_(—)043710) and our sequencing (accession number AY211499). Exons are denoted with solid bars and introns with horizontal lines. Exon lengths are 128, 97, 97, and 109 bps for e36, e37a, e37b, and e38 respectively (accession numbers AY211499 and AY211500). 37a amino acid sequence is CCR1 YKDMYSLLRCIAPPVGLGKNCPRRLAY (SEQ ID NO:46); 37b amino acid is sequence CGRISYNDMFEMLKHMSPPLGLGKKCPARVAY (SEQ ID NO:47) FIG. 13b, Expression pattern of e37b and e37a in RNA isolated from various regions of the adult rat nervous system. SCG, superior cervical ganglia; DRG, dorsal root ganglia; SC, spinal cord; MD, medulla; MB, midbrain; CM, cerebellum; TH, thalamus; HC, hippocampus; CX, cortex. Primers were exon-specific for e37a and e37b. PCR-derived products were separated on a 3% agarose gel. Each lane contains equal amounts of PCR reaction. FIG. 13c and FIG. 13d, Levels of Ca_(V)2.2 mRNA containing e37a and e37b were estimated in P5 (FIG. 13c), and adult (FIG. 13d) DRG tissue by competitive RT-PCR. Each primer pair generated two PCR products, 108 bp from Ca_(V)2.2 cDNA and 135 bp from competitive template. Gel shows products amplified by RT-PCR of RNA isolated from whole DRG (500 pg per reaction=˜5 single cells) for e37a and e37b in the presence of serial dilutions of competitive template (10⁻¹⁸ to 10⁻²² M). In P5 tissue, FIG. 13c, the e37b competitive template product was completely depleted at 5×10⁻²¹ M by the tissue-derived e37b template. The two were approximately equal in intensity at 5×10⁻²⁰ M. The e37a competitive template product was completely depleted at 5×10⁻²² M by the tissue-derived e37a template. The two were approximately equal in intensity at 5×10⁻²¹ M. In adult tissue, FIG. 13d, the e37b competitive template product was completely depleted at 1×10⁻²¹ M by the tissue-derived e37b template. The two were approximately equal in intensity at 5×10⁻²⁰ M. The e37a competitive template product was completely depleted at 1×10⁻²² M by the tissue-derived e37a template. The two were approximately equal in intensity at 5×10⁻²¹ M. These gels are representative of three experiments that gave similar results.

[0042]FIG. 14 shows that exon 37a is preferentially expressed in nociceptive neurons. Single neurons were analyzed by RT-PCR and the expression pattern of e37a correlated with capsaicin-responsiveness. FIG. 14a and FIG. 14b, Histogram summary showing the number of cells expressing e37b and e37a in capsaicin-non-responsive neurons (gray) and responsive neurons (red). e37a-specific primers amplified products in 32 of 58 capsaicin-responsive and 5 of 27 non-responsive neurons. FIG. 14c, Histogram summary of the number of cells expressing e37a, Na_(V)1.8, and both e37a and Na_(V)1.8, in 24 capsaicin-responsive cells. FIG. 14d, Representative gels showing RT-PCR products amplified with e37a, e37b and GAPDH-specific primers from four single cells (lanes 1-4). The capsaicin-responsiveness of each cell is indicated between gels (+ or −). FIG. 14e, Gels showing RT-PCR products amplified with Na_(V)1.8, e37a, and GAPDH-specific primers from four neurons (lanes 1-4). The capsaicin-responsiveness of each neuron is indicated between gels (+ or −).

[0043]FIG. 15 depicts a comparison of calcium channel currents in capsaicin-non-responsive and responsive neurons. FIG. 15a, Average, peak current-voltage relationships for whole cell calcium currents measured in capsaicin-responsive () and non-responsive (∘) neurons of dorsal root ganglia. Average, peak current density and capacitance were, for capsaicin-responsive neurons: 135±19 pA/pF and 18±2 pF, n=20; for capsaicin-non-responsive neurons: 123±17 pA/pF and 27±3 pF, n=9. Curves are fit with the sum of two Boltzmann-GHK functions. Estimated V_(1/2) values were ˜−45 mV and ˜−15 mV for low and high voltage-activated currents, respectively. Upper inset: Representative, low voltage-activated and high voltage-activated whole cell calcium currents activated by voltage steps to −40 mV and −5 mV, respectively, from a holding potential of −80 mV from a capsaicin-non-responsive neuron. Lower inset: Same as upper inset from a capsaicin-responsive neuron. Scale bars: 1 nA, 10 ms. FIG. 15b, Average, peak current voltage relationships for ω-Ctx GVIA-subtracted calcium current in capsaicin-responsive () and non-responsive (∘) neurons. Average, peak current densities were 111±12 pA/pF (n=20) for capsaicin-responsive compared to 72±8 pA/pF (n=9) for non-responsive neurons. These values are significantly different (p<0.05). The ω-Ctx GVIA-sensitive current was 71±2% of the total whole cell calcium current in capsaicin-responsive neurons and 68±2% of whole cell current in non-responsive neurons. Curves are fit with the sum of two Boltzmann-GHK functions. Average V_(1/2) and k values were calculated from fits of individual N-type current-voltage relationships. In capsaicin-non-responsive cells, for the low voltage-activated componefit, V_(1/2) and k values were −25±4 mV and 4.8±0.5 compared to −21+2 mV and 6±0.6 for capsaicin-responsive cells. In capsaicin non-responsive neurons average V_(1/2) and k values were, for the high voltage-activated component: −16+2 mV and 5.4±0.6 compared to −15±1 mV and 5.2±0.3 for capsaicin-responsive cells. Values of V_(1/2) and k were not significantly different between capsaicin-responsive and capsaicin-non-responsive neurons (p>0.05). Inset, Representative ω-Ctx GVIA-sensitive current recorded at −5 mV from a capsaicin-responsive neuron (lower trace) and non-responsive neuron (upper trace). Scale bar: 25 pA/pF, 10 ms. Data are mean±se.

[0044]FIG. 16 show that exon 37a expression is associated with larger N-type currents in capsaicin-responsive neurons. FIG. 16a, Average, peak current-voltage relationships of ω-Ctx GVIA-sensitive calcium current in capsaicin-responsive neurons that contain () and lack (∘) e37a. Average peak current density at 0 mV and capacitance of responsive neurons that contain e37a were 122±11 pA/pF and 20±3 pF (n=8) compared to 76±3 pA/pF and 18±1 pF for neurons that lack e37a (n=8). Peak current densities are significantly greater in neurons containing e37a (p<0.05). Current densities were significantly different between splice isoforms when compared at −10 mV, −5 mV, 0 mV, +5 mV, and +10 mV (p<0.05). Curves are Boltzmann-linear IV fits. Average V_(1/2) and k values are −12.7±1.8 mV and 4.6±0.4, n=8, for neurons containing e37a compared to −13.6±1.7 mV and 5.4±0.3, n=8, for neurons lacking e37a. V_(1/2) and k values are not significantly different between the two groups (p>0.05). Inset shows examples of toxin-subtracted currents from neurons containing () and lacking (∘) exon 37a. Scale bars are 10 ms and 20 pA/pF. FIG. 16b, Averages of time constants estimated from fits of the activation phase of toxin-subtracted N-type currents induced by step depolarizations to indicated test potentials, from capsaicin-responsive neurons containing () and lacking (∘) exon 37a. FIG. 16c, Average time constants estimated from fits of the inactivation kinetics of toxin-subtracted N-type currents induced by step depolarizations to indicated test potentials, from capsaicin-responsive neurons containing () and lacking (∘) exon 37a. FIG. 16d, Representative gels showing RT-PCR products amplified from four single cells (lanes 1-4) with primers specific for e37a, e37b, and GAPDH. Cells were used in the analysis shown in FIG. 16a. Data are mean±se.

[0045]FIG. 17 shows that Ca_(V)2.2e[37a] clones induce N-type currents in Xenopus oocytes that are significantly larger compared to Ca_(V)2.2e[37b]. FIG. 17a, Average peak current-voltage relationships in oocytes expressing Ca_(V)2.2e[37a] ( ) and Ca_(V)2.2e[37b] (∘). After 5 days post injection, average Ca_(V)2.2e[37a] peak currents were 211±2 nA (n=8) compared to 134+4 nA for Ca_(V)2.2e[37b] (n=8). Peak Ca_(V)2.2e[37a] currents were significantly greater than Ca_(V)2.2e[37b] at day 4, 5 and 6 after injection (p<0.05). The dotted line shows the predicted current voltage-relationship of Ca_(V)2.2e[37b] calculated using the Boltzmann activation curve of Ca_(V)2.2e[37a] shown in FIG. 17b. This predicted curve demonstrates that an 8 mV left shift in voltage-dependence of channel activation (see FIG. 17b) is insufficient to account for the significantly larger currents of Ca_(V)2.2e[37a] compared to Ca_(V)2.2e[37b]. Inset: Representative Ca_(V)2.2e[37a] and Ca_(V)2.2e[37b] currents induced by step depolarizations to peak current (−5 mV for Ca_(V)2.2e[37a] and 0 mV for Ca_(V)2.2e[37b]) from a holding potential of −80 mV. Scale bar: 50 nA, 20 ms. V_(1/2) and k values were estimated from Boltzmann-GHK fits to individual data sets. Average V_(1/2) values are −17.9±0.6 mV, n=8, for Ca_(V)2.2e[37a] and −9.7±0.4 mV, n=8, for Ca_(V)2.2e[37b]. k values are 5.3±0.1 for Ca_(V)2.2e[37a] and 5.1±0.1 for Ca_(V)2.2e[37b]. Average, macroscopic activation time constants Tact are 7.2±0.5 ms for Ca_(V)2.2e[37a], n=8, and 10.6±0.5 ms for Ca_(V)2.2 e[37b], n=9. These values are significantly different (p<0.05). Peak currents in oocytes expressing Ca_(V)2.2e[37a] were 186±2 nA (n=4), 211±2 nA (n=8), and 387±20 nA (n=8) at days 4, 5 and 6 days post injection, respectively. Compared to 68±2 nA (n=3), 134±2 nA (n=8), and 204±10 nA (n=8) at 4, 5 and 6 days post injection, respectively, in oocytes expressing Ca_(V)2.2e[37b]. In all cases values between splice isoforms were significantly different on a given day (p<0.05). FIG. 17b, Normalized, averaged activation curves for N-type currents in oocytes expressing Ca_(V)2.2e[37a] () and Ca_(V)2.2e[37b] (∘). Curves were generated from slope conductances calculated from peak current-voltage relationships shown in FIG. 8a, and assuming a reversal potential of +40 mV. Boltzmann functions were fit to individual curves and used to calculate average values for V_(1/2) and k. These were for Ca_(V)2.2e[37a]: −19.7±0.6 mV and 4.4±0.2; and for Ca_(V)2.2e[37b]: −11.7±0.5 mV and 4.7±0.1. V_(1/2) values are significantly different (p<0.05); k values are not significantly different. FIG. 17c, Normalized, averaged steady-state inactivation curves for N-type currents in oocytes expressing Ca_(V)2.2e[37a] () and Ca_(V)2.2e[37b] (∘). Curves were generated from peak currents elicited by 300 ms test pulses to −5 mV (Ca_(V)2.2e[37a], n=12) or 0 mV (Ca_(V)2.2e[37b], n=11) after 20 second conditioning prepulses to voltages ranging from −100 mV to +20 mV. Barium (5 mM) was the charged carrier. Peak currents are plotted as a fraction of the maximum current at the indicated holding potentials. V_(1/2) and k values were estimated from Boltzmann fits to data from individual cells. Average V_(1/2) and k values were for Ca_(V)2.2e[37a]: −72.7±0.8 mV and 8.1±0.4; and for Ca_(V)2.2e[37b]: −72.0±0.4 mV 8.1±0.6. Values are not significantly different. Inactivation kinetics were also measured, Ca_(V)2.2e[37a]: τ_(inact-1)=393±17 ms and τ_(inact-2)=89±5 ms compared to 384±8 ms and 82±2 ms for Ca_(V)2.2e[37b]. Values are not significantly different between splice isoforms. These data are representative of four separate injections. Data are mean±se.

DETAILED DESCRIPTION OF THE INVENTION

[0046] The present invention in one aspect involves the discovery that a particular splice isoform of the N-type calcium channel Ca_(V)2.2α (gene CACNA1B) containing the amino acid sequence encoded by exon 37a, referred to herein as the Ca_(V)2.2e[37a] isoform, is preferentially and specifically expressed in nociceptive neurons. The invention also pertains to the use of these isoforms in drug discovery to identify agents that selectively inhibit the function of N-type calcium channels containing a Ca_(V)2.2e[37a] subunit, particularly in cell-based assays, and agents identified by such methods. The invention also includes agents that modulate expression of the Ca_(V)2.2e[37a] gene transcript (transcription or translation), such as siRNA that selectively reduces expression of Ca_(V)2.2e[37a], and it use in treating conditions that involve this subunit, particularly pain.

[0047] As used herein, Ca_(V)2.2e[37a] refers to any N-type calcium channel Ca_(V)2.2 subunit that contains an amino acid sequence encoded by exon 37a, or nucleic acid molecules encoding such subunits. The human, mouse and rat Ca_(V)2.2e exon 37a-encoded amino acid sequence is presented as SEQ ID NO:45; the equivalent exon in other species can be identified by routine experimental procedures including homology analysis of a species' genomic sequence, transcript sequences (e.g., mRNA), etc. as will be understood by those of skill in the art. N-type calcium channel Ca_(V)2.2 subunits that do not contain exon 37a have been deposited in GenBank under the following accession numbers. TABLE 1 Species Homologs Accession SEQ ID Species number NO Rattus norvegicus AF055477 27, 28 M92905 29, 30 Homo sapiens M94172 31, 32 M94173 33, 34 Mus musculus AF042317 37, 38 U04999 39, 40 Oryctolagus cuniculus (rabbit) D14157 41, 42 Bos taurus AF173882 43, 44

[0048] The human nucleotide sequence of exon 37a (then called exon 42) was identified and deposited under accession number AF238295; it is provided here as SEQ ID NO:35. The amino acid sequence encoded by this sequence is provided here as SEQ ID NO:36. The amino acid sequence (YDPAACCRIHYKDMYSLLRCIAPPVGLGKNCPRRLAYK; SEQ ID NO:36) includes amino acids (double underline) encoded by the 3′ end of exon 41 (nucleotides 1-17) and amino acids (underlined) encoded by exon 42 (nucleotides 4510-4606). Note that amino acid 6 (Cys) is partly encoded by both exon nucleotide sequences.

[0049] Because the present Ca_(V)2.2e[37a] isoform is a splice variant of the N-type calcium channel Ca_(V)2.2 subunit, it is apparent that the invention is meant to embrace N-type calcium channel Ca_(V)2.2 subunit variants which vary by alternative splicing of sequences other than the exon 37a insert (SEQ ID NO:45), and nucleotide sequence encoding such polypeptides. For example, the invention embraces the splice variant polypeptides, and nucleic acid molecules encoding such splice variant polypeptides, as described in U.S. Pat. No. 6,353,091. As shown in the Examples, the Ca_(V)2.2e[37a] subunit is significantly and differentially expressed in certain subsets of neurons that exert different function in different parts of the brain. This opens the possibility for the selective treatment of disorders which involve those parts of the brain.

[0050] The invention involves in one aspect Ca_(V)2.2e[37a] nucleic acids and polypeptides, as well as therapeutics relating thereto. The invention also embraces isolated functionally equivalent variants, useful analogs and fragments of the foregoing nucleic acids and polypeptides; complements of the foregoing nucleic acids; and molecules which selectively bind the foregoing nucleic acids and polypeptides.

[0051] The Ca_(V)2.2e[37a] nucleic acids and polypeptides of the invention are isolated. The term “isolated”, as used herein in reference to a nucleic acid molecule, means a nucleic acid sequence: (i) amplified in vitro by, for example, polymerase chain reaction (PCR); (ii) synthesized by, for example, chemical synthesis; (iii) recombinantly produced by cloning; or (iv) purified, as by cleavage and electrophoretic or chromatographic separation. The term “isolated”, as used herein in reference to a polypeptide, means a polypeptide encoded by an isolated nucleic acid sequence, as well as polypeptides synthesized by, for example, chemical synthetic methods, and polypeptides separated from biological materials, and then purified, using conventional protein analytical or preparatory procedures, to an extent that permits them to be used according to the methods described herein.

[0052] As used herein a Ca_(V)2.2e[37a] nucleic acid refers to an isolated nucleic acid molecule which codes for a Ca_(V)2.2 subunit protein that includes exon 37a. Ca_(V)2.2e[37a] nucleic acids are those nucleic acid molecules which code for Ca_(V)2.2e[37a] polypeptides which include the sequence of SEQ ID NO: 45. The Ca_(V)2.2e[37a] nucleic acids of the invention also include alleles and species homologs of the foregoing nucleic acids, as well as fragments of the foregoing nucleic acids, provided that the allele, species isoform or fragment contains exon 37a (i.e., the pertinent exon of the particular species that is homologous to those described herein). Such fragments can be used, for example, as probes in hybridization assays, as primers in a polymerase chain reaction (PCR), and for reconbination with exon 37b containing nucleic acids. In a preferred embodiment, exon 37a-specific fragments and their complements can be used in the preparation of double stranded RNA molecules (such as siRNA molecules and hairpins) useful for inhibition of expression by RNA interference (RNAi). Preferred Ca_(V)2.2e[37a] nucleic acids include nucleotides 4510-4606 of SEQ ID NO:35 (Accession number AF238295). Complements of the foregoing nucleic acids also are embraced by the invention.

[0053] As used herein “Ca_(V)2.2e[37a] activity” refers to an ability of a molecule to modulate voltage regulated calcium influx. As shown in the Examples, neurons and other cells that express N-type calcium channels containing Ca_(V)2.2e[37a] have significantly larger N-type currents. Thus, a molecule which inhibits Ca_(V)2.2e[37a] activity (an antagonist) is one which inhibits voltage regulated calcium influx via this calcium channel and a molecule which increases Ca_(V)2.2e[37a] activity (an agonist) is one which increases voltage regulated calcium influx via this calcium channel. Changes in Ca_(V)2.2e[37a] activity can be measured by changes in voltage regulated calcium influx by in vitro assays such as those disclosed herein, including patch-clamp assays, and other assays known to those of skill in the art, such as assays employing calcium sensitive fluorescent compounds such as fura-2.

[0054] Alleles of the Ca_(V)2.2e[37a] nucleic acids of the invention can be identified by conventional techniques. For example, alleles of Ca_(V)2.2e[37a] can be isolated by hybridizing a probe which includes nucleotides 4510-4606 of SEQ ID NO:35, or another nucleotide sequence that encodes SEQ ID NO:45 (except the first amino acid, which as noted herein is encoded partly by exon 36 and partly by exon 37a), under stringent conditions with a cDNA library and selecting positive clones. Thus, an aspect of the invention is those nucleic acid sequences which code for Ca_(V)2.2e[37a] polypeptides and which hybridize to a nucleic acid molecule consisting of Ca_(V)2.2 exon 37a under stringent conditions. The term “stringent conditions” as used herein refers to parameters with which the art is familiar. Nucleic acid hybridization parameters may be found in references which compile such methods, e.g. Molecular Cloning: A Laboratory Manual, J. Sambrook, et al., eds., Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989, or Current Protocols in Molecular Biology, F. M. Ausubel, et al., eds., John Wiley & Sons, Inc., New York. More specifically, stringent conditions, as used herein, refers, for example, to hybridization at 65° C. in hybridization buffer (3.5×SSC, 0.02% Ficoll, 0.02% polyvinyl pyrrolidone, 0.02% Bovine Serum Albumin, 2.5 mM NaH₂PO₄(pH7), 0.5% SDS, 2 mM EDTA). SSC is 0.15M sodium chloride/0.015M sodium citrate, pH7; SDS is sodium dodecyl sulphate; and EDTA is ethylenediaminetetracetic acid. After hybridization, the membrane upon which the DNA is transferred is washed at 2×SSC at room temperature and then at 0.1×SSC/0.1×SDS at temperatures up to 65° C.

[0055] There are other conditions, reagents, and so forth which can be used, which result in a similar degree of stringency. The skilled artisan will be familiar with such conditions, and thus they are not given here. It will be understood, however, that the skilled artisan will be able to manipulate the conditions in a manner to permit the clear identification of alleles of Ca_(V)2.2e[37a] nucleic acids of the invention. The skilled artisan also is familiar with the methodology for screening cells and libraries for expression of such molecules which then are routinely isolated, followed by isolation of the pertinent nucleic acid molecule and sequencing.

[0056] In screening for Ca_(V)2.2e[37a] nucleic acids, nucleic acid amplification techniques such as PCR can be performed as known to one of ordinary skill in the art. In addition, hybridization techniques such as Southern and Northern blots may be performed using the foregoing stringent conditions, together with a labeled (e.g., fluorescently, radioactively) probe. After washing the membrane to which the DNA is finally transferred, the membrane can be placed against various photon capture devices (e.g., phosphorimager) or X-ray film to detect the radioactive signal.

[0057] Alleles of Ca_(V)2.2e[37a] nucleic acids also can be identified using in silico techniques of database mining, sequence comparison, etc. as will be known to one of ordinary skill in the art.

[0058] The Ca_(V)2.2e[37a] nucleic acids of the invention also include degenerate nucleic acids which include alternative codons to those present in the native materials. For example, serine residues are encoded by the codons TCA, AGT, TCC, TCG, TCT and AGC. Each of the six codons is equivalent for the purposes of encoding a serine residue. Thus, it will be apparent to one of ordinary skill in the art that any of the serine-encoding nucleotide triplets may be employed to direct the protein synthesis apparatus, in vitro or in vivo, to incorporate a serine residue into an elongating Ca_(V)2.2e[37a] polypeptide. Similarly, nucleotide sequence triplets which encode other amino acid residues include, but are not limited to: CCA, CCC, CCG and CCT (proline codons); CGA, CGC, CGG, CGT, AGA and AGG (arginine codons); ACA, ACC, ACG and ACT (threonine codons); AAC and AAT (asparagine codons); and ATA, ATC and ATT (isoleucine codons). Other amino acid residues may be encoded similarly by multiple nucleotide sequences. Thus, the invention embraces degenerate nucleic acids that differ from the biologically isolated nucleic acids in codon sequence due to the degeneracy of the genetic code.

[0059] The invention also provides isolated fragments of Ca_(V)2.2e[37a] nucleic acids, which include at least part of the nucleotide sequence that encodes SEQ ID NO:45. The fragments can be used as probes in Southern blot assays to identify such nucleic acids, or can be used in amplification assays such as those employing PCR. Smaller fragments are those comprising 12, 13, 14, 15, 16, 17, 18, 20, 22, 25, 30, 40, 50, or 75 nucleotides, and every integer therebetween and are useful e.g. as primers for nucleic acid amplification procedures. As known to those skilled in the art, larger probes such as 100, 200, 250, 300, 400 or more nucleotides are preferred for certain uses such as Southern blots, while smaller fragments will be preferred for uses such as PCR. Fragments also can be used to produce fusion proteins for generating antibodies or determining binding of the polypeptide fragments. Likewise, fragments can be employed to produce non-fused fragments of the Ca_(V)2.2e[37a] polypeptides, useful, for example, in the preparation of antibodies, in immunoassays, and the like. The foregoing nucleic acid fragments further can be used as antisense molecules or siRNA molecules to inhibit the expression of Ca_(V)2.2e[37a] nucleic acids and polypeptides, particularly for therapeutic purposes as described in greater detail below.

[0060] The invention also includes functionally equivalent variants of the Ca_(V)2.2e[37a], which include variant nucleic acids and polypeptides that retain one or more of the functional properties of the Ca_(V)2.2e[37a], such as the different current densities as described in greater detail below. For example, functionally equivalent variants include a Ca_(V)2.2e[37a] molecule which has had a portion of the extracellular domain removed or replaced by a similar domain from another calcium channel α₁ subunit (e.g. a “domain-swapping” variant). Other functionally equivalent variants will be known to one of ordinary skill in the art, as will methods for preparing such variants. The activity of a functionally equivalent variant can be determined using the methods provided, e.g., herein, in Lin et al., Neuron 18:153-166, 1997, and in U.S. Pat. No. 5,429,921. Such variants are useful, inter alia, in assays for identification of compounds which bind and/or regulate the calcium influx function of the Ca_(V)2.2e[37a], and for determining the portions of the Ca_(V)2.2e[37a] which are required for calcium influx activity.

[0061] Variants that are non-functional also can be prepared as described above. Such variants are useful, for example, as negative controls in experiments testing subunit activity, and as inhibition of nociceptive-specific N-type calcium channel activity.

[0062] A Ca_(V)2.2e[37a] nucleic acid, in one embodiment, is operably linked to a gene expression sequence which directs the expression of the Ca_(V)2.2e[37a] nucleic acid within a eukaryotic or prokaryotic cell. The “gene expression sequence” is any regulatory nucleotide sequence, such as a promoter sequence or promoter-enhancer combination, which facilitates the efficient transcription and translation of the Ca_(V)2.2e[37a] nucleic acid to which it is operably linked. The gene expression sequence may, for example, be a mammalian or viral promoter, such as a constitutive or inducible promoter. Constitutive mammalian promoters include, but are not limited to, the promoters for the following genes: hypoxanthine phosphoribosyl transferase (HPRT), adenosine deaminase, pyruvate kinase, β-actin promoter and other constitutive promoters. Exemplary viral promoters which function constitutively in eukaryotic cells include, for example, promoters from the simian virus, papilloma virus, adenovirus, human immunodeficiency virus (HIV), Rous sarcoma virus, cytomegalovirus, the long terminal repeats (LTR) of Moloney murine leukemia virus and other retroviruses, and the thymidine kinase promoter of herpes simplex virus. Other constitutive promoters are known to those of ordinary skill in the art. The promoters useful as gene expression sequences of the invention also include inducible promoters. Inducible promoters are expressed in the presence of an inducing agent. For example, the metallothionein promoter is induced to promote transcription and translation in the presence of certain metal ions. Other inducible promoters are known to those of ordinary skill in the art.

[0063] In general, the gene expression sequence shall include, as necessary, 5′ non-transcribing and 5′ non-translating sequences involved with the initiation of transcription and translation, respectively, such as a TATA box, capping sequence, CAAT sequence, and the like. Especially, such 5′ non-transcribing sequences will include a promoter region which includes a promoter sequence for transcriptional control of the operably joined Ca_(V)2.2e[37a] nucleic acid. The gene expression sequences optionally includes enhancer sequences or upstream activator sequences as desired.

[0064] The Ca_(V)2.2e[37a] nucleic acid sequence and the gene expression sequence are said to be “operably linked” when they are covalently linked in such a way as to place the transcription and/or translation of the Ca_(V)2.2e[37a] coding sequence under the influence or control of the gene expression sequence. If it is desired that the Ca_(V)2.2e[37a] sequence be translated into a functional protein, two DNA sequences are said to be operably linked if induction of a promoter in the 5′ gene expression sequence results in the transcription of the Ca_(V)2.2e[37a] sequence and if the nature of the linkage between the two DNA sequences does not (1) result in the introduction of a frame-shift mutation, (2) interfere with the ability of the promoter region to direct the transcription of the Ca_(V)2.2e[37a] sequence, or (3) interfere with the ability of the corresponding RNA transcript to be translated into a protein. Thus, a gene expression sequence would be operably linked to a Ca_(V)2.2e[37a] nucleic acid sequence if the gene expression sequence were capable of effecting transcription of that Ca_(V)2.2e[37a] nucleic acid sequence such that the resulting trariscript might be translated into the desired protein or polypeptide.

[0065] The Ca_(V)2.2e[37a] nucleic acid and the Ca_(V)2.2e[37a] polypeptide (including the Ca_(V)2.2e[37a] inhibitors described below) of the invention can be delivered to the eukaryotic or prokaryotic cell alone or in association with a vector. In its broadest sense, a “vector” is any vehicle capable of facilitating: (1) delivery of a Ca_(V)2.2e[37a] nucleic acid or polypeptide to a target cell or (2) uptake of a Ca_(V)2.2e[37a] nucleic acid or polypeptide by a target cell. Preferably, the vectors transport the Ca_(V)2.2e[37a] nucleic acid or polypeptide into the target cell with reduced degradation relative to the extent of degradation that would result in the absence of the vector. Optionally, a “targeting ligand” can be attached to the vector to selectively deliver the vector to a cell which expresses on its surface the cognate receptor (e.g. a receptor, an antigen recognized by an antibody) for the targeting ligand. In this manner, the vector (containing a Ca_(V)2.2e[37a] nucleic acid or a Ca_(V)2.2e[37a] polypeptide) can be selectively delivered to a specific cell. In general, the vectors useful in the invention are divided into two classes: biological vectors and chemical/physical vectors. Biological vectors are more useful for delivery/uptake of Ca_(V)2.2e[37a] nucleic acids to/by a target cell. Chemical/physical vectors are more useful for delivery/uptake of Ca_(V)2.2e[37a] nucleic acids or Ca_(V)2.2e[37a] proteins to/by a target cell.

[0066] Biological vectors include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the nucleic acid sequences of the invention, and free nucleic acid fragments which can be attached to the nucleic acid sequences of the invention. Viral vectors are a preferred type of biological vector and include, but are not limited to, nucleic acid sequences from the following viruses: retroviruses, such as Moloney murine leukemia virus; Harvey murine sarcoma virus; murine mammary tumor virus; Rous sarcoma virus; adenovirus; adeno-associated virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; and polio virus. One can readily employ other vectors not named but known in the art.

[0067] Preferred viral vectors are based on non-cytopathic eukaryotic viruses in which non-essential genes have been replaced with the gene of interest. Non-cytopathic viruses include retroviruses, the life cycle of which involves reverse transcription of genomic viral RNA into DNA with subsequent proviral integration into host cellular DNA. In general, the retroviruses are replication-deficient (i.e., capable of directing synthesis of the desired proteins, but incapable of manufacturing an infectious particle). Such genetically altered retroviral expression vectors have general utility for the high-efficiency transduction of genes in vivo. Standard protocols for producing replication-deficient retroviruses (including the steps of incorporation of exogenous genetic material into a plasmid, transfection of a packaging cell line with plasmid, production of recombinant retroviruses by the packaging cell line, collection of viral particles from tissue culture media, and infection of the target cells with viral particles) are provided in Kriegler, M., “Gene Transfer and Expression, A Laboratory Manual,” W.H. Freeman C.O., New York (1990) and Murry, E. J. Ed. “Methods in Molecular Biology,” vol. 7, Humana Press, Inc., Clifton, N.J. (1991).

[0068] Another preferred virus for certain applications is the adeno-associated virus, a double-stranded DNA virus. The adeno-associated virus can be engineered to be replication-deficient and is capable of infecting a wide range of cell types and species. It further has advantages, such as heat and lipid solvent stability; high transduction frequencies in cells of diverse lineages, including hemopoietic cells; and lack of superinfection inhibition thus allowing multiple series of transductions. Reportedly, the adeno-associated virus can integrate into human cellular DNA in a site-specific manner, thereby minimizing the possibility of insertional mutagenesis and variability of inserted gene expression. In addition, wild-type adeno-associated virus infections have been followed in tissue culture for greater than 100 passages in the absence of selective pressure, implying that the adeno-associated virus genomic integration is a relatively stable event. The adeno-associated virus can also function in an extrachromosomal fashion.

[0069] Expression vectors containing all the necessary elements for expression are commercially available and known to those skilled in the art. See, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press, 1989. Cells are genetically engineered by the introduction into the cells of heterologous DNA (RNA) encoding a Ca_(V)2.2e[37a] polypeptide or fragment or variant thereof. That heterologous DNA (RNA) is placed under operable control of transcriptional elements to permit the expression of the heterologous DNA in the host cell.

[0070] Preferred systems for mRNA expression in mammalian cells are those such as the pcDNA series of vectors (available from Invitrogen, Carlsbad, Calif.) that contain a selectable marker such as a gene that confers G418 resistance (which facilitates the selection of stably transfected cell lines) and the human cytomegaloviius (CMV) enhancer-promoter sequences. Additionally, suitable for expression in primate or canine cell lines is the pCEP4 vector (Invitrogen), which contains an Epstein Barr virus (EBV) origin of replication, facilitating the maintenance of plasmid as a multicopy extrachromosomal element. Another expression vector is the pEF-BOS plasmid containing the promoter of polypeptide Elongation Factor 1α, which stimulates efficiently transcription in vitro. The plasmid is described by Mishizuma and Nagata (Nuc. Acids Res. 18:5322, 1990), and its use in transfection experiments is disclosed by, for example, Demoulin (Mol. Cell. Biol. 16:4710-4716, 1996). Still another preferred expression vector is an adenovirus, described by Stratford-Perricaudet, which is defective for E1 and E3 proteins (J. Clin. Invest. 90:626-630, 1992).

[0071] In addition to the biological vectors, chemical/physical vectors may be used to deliver a Ca_(V)2.2e[37a] nucleic acid or polypeptide to a target cell and facilitate uptake thereby. As used herein, a “chemical/physical vector” refers to a natural or synthetic molecule, other than those derived from bacteriological or viral sources, capable of delivering the isolated Ca_(V)2.2e[37a] nucleic acid or polypeptide to a cell.

[0072] A preferred chemical/physical vector of the invention is a colloidal dispersion system. Colloidal dispersion systems include lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. A preferred colloidal system of the invention is a liposome. Liposomes are artificial membrane vesicles which are useful as a delivery vector in vivo or in vitro. It has been shown that large unilamellar vesicles (LUV), which range in size from 0.2-4.0μ can encapsulate large macromolecules. RNA, DNA, and intact virions can be encapsulated within the aqueous interior and be delivered to cells in a biologically active form (Fraley, et al., Trends Biochem. Sci., v. 6, p. 77 (1981)). In order for a liposome to be an efficient nucleic acid transfer vector, one or more of the following characteristics should be present: (1) encapsulation of the nucleic acid of interest at high efficiency with retention of biological activity; (2) preferential and substantial binding to a target cell in comparison to non-target cells; (3) delivery of the aqueous contents of the vesicle to the target cell cytoplasm at high efficiency; and (4) accurate and effective expression of genetic information.

[0073] Liposomes may be targeted to a particular tissue by coupling the liposome to a specific ligand such as a monoclonal antibody, sugar, glycolipid, or protein. Ligands which may be useful for targeting a liposome to a particular cell will depend on the particular cell or tissue type. Additionally when the vector encapsulates a nucleic acid, the vector may be coupled to a nuclear targeting peptide, which will direct the Ca_(V)2.2e[37a] nucleic acid to the nucleus of the host cell.

[0074] Liposomes are commercially available from Gibco BRL, for example, as LIPOFECTIN™ and LIPOFECTACE™, which are formed of cationic lipids such as N-[1-(2, 3 dioleyloxy)-propyl]-N,N, N-trimethylammonium chloride (DOTMA) and dimethyl dioctadecylammonium bromide (DDAB). Methods for making liposomes are well known in the art and have been described in many publications. Liposomes also have been reviewed by Gregoriadis, G. in Trends in Biotechnology, V. 3, p. 235-241 (1985).

[0075] Other exemplary compositions that can be used to facilitate uptake by a target cell of the Ca_(V)2.2e[37a] nucleic acids include calcium phosphate and other chemical mediators of intracellular transport, microinjection compositions, electroporation and homologous recombination compositions (e.g., for integrating a Ca_(V)2.2e[37a] nucleic acid into a preselected location within a target cell chromosome).

[0076] The invention also embraces so-called expression kits, which allow the artisan to prepare a desired expression vector or vectors. Such expression kits include at least separate portions of the previously discussed coding sequences. Other components may be added, as desired, as long as the previously mentioned sequences, which are required, are included.

[0077] It will also be recognized that the invention embraces the use of the Ca_(V)2.2e[37a] cDNA sequences in expression vectors, as well as to transfect host cells and cell lines, be these prokaryotic (e.g., E. coli), or eukaryotic (e.g., neurons, oocytes, COS cells, yeast expression systems and recombinant baculovirus expression in insect cells). Especially useful are mammalian cells such as human, pig, goat, primate, mouse, rat, etc., which can be used for the identification of molecules that regulate the function of Ca_(V)2.2e[37a] selectively (e.g., by screening chemical compounds libraries) They may be of a wide variety of tissue types, and include primary cells and cell lines. Specific examples include neuronal cells including PC12 cells, Xenopus oocytes, bone marrow stem cells and embryonic stem cells. The expression vectors require that the pertinent sequence, i.e., those nucleic acids described supra, be operably linked to a promoter.

[0078] The invention also provides isolated Ca_(V)2.2e[37a] polypeptides which include the amino acid sequence of SEQ ID NO:45, encoded by the Ca_(V)2.2e[37a] nucleic acids described above. The preferred Ca_(V)2.2e[37a] polypeptide has the amino acid sequence of any of the N-type calcium channel subunit proteins disclosed herein (see e.g., Table 1), with the amino acid sequence of exon 37a (SEQ ID NO:45) substituted for that of exon 37b. Ca_(V)2.2e[37a] polypeptides also embrace alleles, isoforms (such as splice variants), functionally equivalent variants and analogs (those non-allelic polypeptides which vary in amino acid sequence from SEQ ID NO:45 by 1, 2, 3, 4, or 5 amino acids) provided that such polypeptides retain Ca_(V)2.2e[37a] activity. Non-functional variants also are embraced by the invention; these are useful as antagonists of calcium channel function, as negative controls in assays, and the like. Such alleles, isoforms, variants, analogs and fragments are useful, for example, alone or as fusion proteins for a variety of purposes such as to generate antibodies, or as a component of an immunoassay.

[0079] Fragments of a polypeptide preferably are those fragments which retain a distinct functional capability of the Ca_(V)2.2e[37a] polypeptide, in particular voltage regulated calcium influx. Other functional capabilities which can be retained in an allele, isoform, variant, analog or fragment (generically called “variant” herein) of a Ca_(V)2.2e[37a] polypeptide include interaction with antibodies and interaction with other polypeptides (such as other subunits of the human N-type calcium channel). Those skilled in the art are well versed in methods for selecting alleles, isoforms, variants, analogs or fragments which retain a functional capability of the Ca_(V)2.2e[37a]. Confirmation of the functional capability of the fragment can be carried out by synthesis of the fragment and testing of the capability according to standard methods. For example, to test the voltage regulated calcium influx of a Ca_(V)2.2e[37a] fragment, one inserts or expresses the fragment in a cell in which calcium influx can be measured. Such methods, which are standard in the art, are described further in the examples.

[0080] The invention embraces variants of the Ca_(V)2.2e[37a] polypeptides described above. As used herein, a “variant” of a Ca_(V)2.2e[37a] polypeptide is a polypeptide which contains one or more modifications to the primary amino acid sequence of a Ca_(V)2.2e[37a] polypeptide. Modifications which create a Ca_(V)2.2e[37a] variant can be made to a Ca_(V)2.2e[37a] polypeptide for a variety of reasons, including 1) to reduce or eliminate an activity of a Ca_(V)2.2e[37a] polypeptide, such as voltage gated calcium influx; 2) to enhance a property of a Ca_(V)2.2e[37a] polypeptide, such as protein stability in an expression system or the stability of protein-protein binding; 3) to provide a novel activity or property to a Ca_(V)2.2e[37a] polypeptide, such as addition of an antigenic epitope or addition of a detectable moiety; or 4) to establish that an amino acid substitution, such as a different sequence encoded by an alternatively spliced exon, does or does not affect voltage gated calcium influx. Modifications to a Ca_(V)2.2e[37a] polypeptide are typically made to the nucleic acid which encodes the Ca_(V)2.2e[37a] polypeptide, and can include deletions, point mutations, truncations, amino acid substitutions and additions of amino acids or non-amino acid moieties. Alternatively, modifications can be made directly to the polypeptide, such as by cleavage, addition of a linker molecule, addition of a detectable moiety, such as biotin, addition of a fatty acid, and the like. Modifications also embrace fusion proteins comprising all or part of the Ca_(V)2.2e[37a] amino acid sequence, but always including the amino acid sequence encoded by exon 37a.

[0081] One of skill in the art will be familiar with methods for predicting the effect on protein conformation of a change in protein sequence, and can thus “design” a variant Ca_(V)2.2e[37a] according to known methods. One example of such a method is described by Dahiyat and Mayo in Science 278:82-87, 1997, whereby proteins can be designed de novo. Additional computer-based modeling methods also are available. The method can be applied to a known protein to vary a only a portion of the polypeptide sequence. By applying the computational methods of Dahiyat and Mayo, specific variants of a Ca_(V)2.2e[37a] polypeptide can be proposed and tested to determine whether the variant retains a desired conformation.

[0082] Variants include Ca_(V)2.2e[37a] polypeptides which are modified specifically to alter a feature of the polypeptide unrelated to its physiological activity. For example, cysteine residues can be substituted or deleted to prevent unwanted disulfide linkages. Similarly, certain amino acids can be changed to enhance expression of a Ca_(V)2.2e[37a] polypeptide by eliminating proteolysis by proteases in an expression system (e.g., dibasic amino acid residues in yeast expression systems in which KEX2 protease activity is present).

[0083] Mutations of a nucleic acid which encode a Ca_(V)2.2e[37a] polypeptide preferably preserve the amino acid reading frame of the coding sequence, and preferably do not create regions in the nucleic acid which are likely to hybridize to form secondary structures, such as hairpins or loops, which can be deleterious to expression of the variant polypeptide.

[0084] Mutations can be made by selecting an amino acid substitution, or by random mutagenesis (e.g., directed molecular evolution, optionally of a selected site) in a nucleic acid which encodes the polypeptide. Variant polypeptides are then expressed and tested for one or more activities to determine which mutation provides a variant polypeptide with a desired property. Further mutations can be made to variants (or to non-variant Ca_(V)2.2e[37a] polypeptides) which are silent as to the amino acid sequence of the polypeptide, but which provide preferred codons for translation in a particular host. The preferred codons for translation of a nucleic acid in, e.g., E. coli, are well known to those of ordinary skill in the art. Still other mutations can be made to the noncoding sequences of a Ca_(V)2.2e[37a] gene or cDNA clone to enhance expression of the polypeptide.

[0085] The activity of variants of Ca_(V)2.2e[37a] polypeptides can be tested by cloning the gene encoding the variant Ca_(V)2.2e[37a] polypeptide into a bacterial or mammalian expression vector, introducing the vector into an appropriate host cell, expressing the variant Ca_(V)2.2e[37a] polypeptide, and testing for a functional capability of the Ca_(V)2.2e[37a] polypeptides as disclosed herein. For example, the variant Ca_(V)2.2e[37a] polypeptide can be tested for ability to provide voltage regulated calcium influx, as set forth below in the examples. Preparation of other variant polypeptides may favor testing of other activities, as will be known to one of ordinary skill in the art.

[0086] The skilled artisan will also realize that conservative amino acid substitutions may be made in Ca_(V)2.2e[37a] polypeptides to provide functionally equivalent variants of the foregoing polypeptides, i.e. variants which retain the functional capabilities of the Ca_(V)2.2e[37a] polypeptides. As used herein, a “conservative amino acid substitution” refers to an amino acid substitution which does not alter the relative charge or size characteristics of the polypeptide in which the amino acid substitution is made. Variants can be prepared according to methods for altering polypeptide sequence known to one of ordinary skill in the art such as are found in references which compile such methods, e.g. Molecular Cloning: A Laboratory Manual, J. Sambrook, et al., eds., Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989, or Current Protocols in Molecular Biology, F. M. Ausubel, et al., eds., John Wiley & Sons, Inc., New York. Exemplary functionally equivalent variants of the Ca_(V)2.2e[37a] polypeptides include conservative amino acid substitutions of the Ca_(V)2.2 sequences described herein, but excluding the portion of the polypeptide consisting of the amino acid sequence encoded by exon 37a. Other variants can include amino acid substitutions of the exon 37a-encoded sequence, which may be useful for determining which amino acid residues are of importance in the functional activity of Ca_(V)2.2e[37a] protein; such variants can be used in assays to screen molecules for Ca_(V)2.2e[37a] antagonist or agonist activity as well. Exemplary conservative substitutions of amino acids include substitutions made amongst amino acids within the following groups: (a) M, I, L, V; (b) F, Y, W; (c) K, R, H; (d) A, G; (e) S, T; (f) Q, N; and (g) E, D.

[0087] Conservative amino-acid substitutions in the amino acid sequence of Ca_(V)2.2e[37a] polypeptide to produce functionally equivalent variants of Ca_(V)2.2e[37a] polypeptides typically are made by alteration of a nucleic acid sequence encoding Ca_(V)2.2e[37a] polypeptides (e.g., nucleotides 5212-5308 of SEQ ID NO:23). Such substitutions can be made by a variety of methods known to one of ordinary skill in the art. For example, amino acid substitutions may be made by PCR-directed mutation, site-directed mutagenesis according to the method of Kunkel (Proc. Nat. Acad. Sci. U.S.A. 82: 488-492, 1985), or by chemical synthesis of a gene encoding a Ca_(V)2.2e[37a] polypeptide. Where amino acid substitutions are made to a small unique fragment of a Ca_(V)2.2e[37a] polypeptide, such as a specific domain, the substitutions can be made by directly synthesizing the peptide. The activity of functionally equivalent variants of Ca_(V)2.2e[37a] polypeptides can be tested by cloning the gene encoding the altered Ca_(V)2.2e[37a] polypeptide into a bacterial or mammalian expression vector, introducing the vector into an appropriate host cell, expressing the altered Ca_(V)2.2e[37a] polypeptide, and testing for the ability of the Ca_(V)2.2e[37a] polypeptide to transduce voltage regulated calcium influx. Peptides which are chemically synthesized can be tested directly for function.

[0088] A variety of methodologies well-known to the skilled practitioner can be utilized to obtain isolated Ca_(V)2.2e[37a] molecules. The polypeptide may be purified from cells which naturally produce the polypeptide by chromatographic means or immunological recognition. Alternatively, an expression vector may be introduced into cells to cause production of the polypeptide. In another method, mRNA transcripts may be microinjected or otherwise introduced into cells to cause production of the encoded polypeptide. Translation of mRNA in cell-free extracts such as the reticulocyte lysate system also may be used to produce polypeptide. Those skilled in the art also can readily follow known methods for isolating Ca_(V)2.2e[37a] polypeptides. These include, but are not limited to, immunochromatography, HPLC, size-exclusion chromatography, ion-exchange chromatography and immune-affinity chromatography.

[0089] The invention also embraces agents which bind selectively to the Ca_(V)2.2e[37a] molecules (having or encoding SEQ ID NO:45) and agents which bind preferentially to the Ca_(V)2.2e[37a] (having or encoding SEQ ID NO:45) as well as agents which bind to variants and fragments of the polypeptides and nucleic acids as described herein. Selective binding means that the agent binds to the Ca_(V)2.2e[37a] but not to N-type calcium channel non-Ca_(V)2.2e[37a] subunits (i.e., those subunits which do not have or encode SEQ ID NO:45). Preferential binding means that the agent binds more to the Ca_(V)2.2e[37a] than to N-type calcium channel non-Ca_(V)2.2e[37a] subunits, e.g., the agent binds with greater affinity or avidity to the Ca_(V)2.2e[37a] having or encoding SEQ ID NO:45. The agents include polypeptides which bind to Ca_(V)2.2e[37a], antisense nucleic acids, and siRNA molecules. The agents can inhibit or increase Ca_(V)2.2e[37a] activity (antagonists and agonists, respectively).

[0090] Some of the agents are inhibitors. A Ca_(V)2.2e[37a] inhibitor is an agent that inhibits Ca_(V)2.2e[37a] mediated voltage gated calcium influx. Ca_(V)2.2e[37a] inhibitors include dominant negative peptides and modified known N-type calcium channel inhibitors including modified ω-conotoxin peptides, such as analogs of ziconotide (SNX-111). Small organic molecule calcium channel inhibitors, such as fluspirilene, NNC 09-0026(−)-trans-1-butyl-4-(4-dimethylaminophenyl)-3-[(4-trifluoromethyl-phenoxy) methyl] piperidinedihydrochloride); SB 201823-A (4-[2-(3,4-dichlorophenoxy)ethyl]-1-pentyl piperidinehydrochloride); NS 649 (2-amino-1-(2,5-dimethoxyphenyl)-5-trifluoromethyl benzimidazole); CNS 1237 (N-acenaphthyl-N′-4-methoxynaphth-1-yl guanidine), riluzole and analogs thereof may also exhibit specificity for the Ca_(V)2.2e[37a].

[0091] The invention facilitates the development of analogs of these and other calcium channel inhibitors by providing a specific target molecule that is selectively expressed in nociceptive inhibitors. Useful assays are described below and in the Examples in greater detail. The assays of the invention permit the selection of inhibitors, including those mentioned above, analogs and derivatives of those mentioned above, and other molecules that are selective or preferential antagonists (or agonists) of Ca_(V)2.2e[37a].

[0092] Calcium influx assays can be performed to screen and/or determine whether a Ca_(V)2.2e[37a] inhibitor has the ability to inhibit Ca_(V)2.2e[37a] activity, and whether the inhibition is selective or preferential. As used herein, “inhibit” refers to inhibiting by at least 10% voltage gated calcium influx, preferably inhibiting by at least 25% voltage gated calcium influx, and more preferably inhibiting by at least 40% voltage gated calcium influx mediated by Ca_(V)2.2e[37a] as measured by any of the methods well known in the art. An exemplary assay of voltage gated calcium influx is described below in the Examples. By “selective inhibition” is meant that the inhibitor inhibits voltage gated calcium influx mediated by Ca_(V)2.2e[37a] but does not significantly inhibit voltage gated calcium influx mediated by the Ca_(V)2.2e[37b] alternatively spliced subunit. By “preferential inhibition” is meant that the inhibitor inhibits voltage gated calcium influx mediated by Ca_(V)2.2e[37a] by at least about 5% more that voltage gated calcium influx mediated by the Ca_(V)2.2e[37b] alternatively spliced subunit. Preferably, the preferential inhibition is at least about 10% more for Ca_(V)2.2e[37a], more preferably at least about 20% more for Ca_(V)2.2e[37a], still more preferably at least about 30% more for Ca_(V)2.2e[37a], yet more preferably at least about 40% more for Ca_(V)2.2e[37a], and most preferably at least about 50% more for Ca_(V)2.2e[37a]. Greater differences in inhibition of Ca_(V)2.2e[37a] than Ca_(V)2.2e[37b] is contemplated, from 51% all the way up to about 99%, at which point the inhibition may be considered selective.

[0093] Inhibitors may selectively or preferentially inhibit Ca_(V)2.2e[37a] based on the state of depolarization of the membrane with which the Ca_(V)2.2e[37a] is associated. It is well known that certain compounds preferentially bind to voltage-gated calcium channels at particular voltages. For example, dihydropyridine compounds preferentially bind to L-type voltage-gated calcium channels when the membrane is depolarized. Bean (Proc. Nat'l. Acad. Sci. 81:6388, 1984) described the binding of nitrendipine to cardiac L-type channels only when the membrane is depolarized. Similar results have been found for nimodipine action in sensory neurons (McCarthy & TanPiengco, J. Neurosci. 12:2225, 1992).

[0094] Activators of Ca_(V)2.2e[37a] activity also are enhanced by the invention. Activators may be identified and/or tested using methods described above for inhibitors.

[0095] In screening for modulators of Ca_(V)2.2e[37a], including inhibitors and activators (i.e. antagonists and agonists), it is preferred that compounds (e.g., libraries of potential channel inhibitors) are tested for modulation of Ca_(V)2.2e[37a] activity at a variety of voltages which cause partial or complete membrane depolarization, or hyperpolarization. These assays are conducted according to standard procedures of testing calcium channel function (e.g. patch clamping, fluorescent Ca²⁺ influx assays) which require no more than routine experimentation. Using such methods, modulators of Ca_(V)2.2e[37a] activity which are active at particular voltages (e.g., complete membrane depolarization) can be identified. Such compounds are useful for selectively modulating calcium channel activity in conditions which may display voltage dependence. For example, following a stroke membranes are depolarized and such compounds may be active in selectively blocking calcium channel activity for treatment of stroke. Other uses will be apparent to one of ordinary skill in the art.

[0096] The invention further provides efficient methods of identifying pharmacological agents or lead compounds for agents useful in the treatment of conditions associated with voltage gated cell calcium influx mediated by calcium channels containing Ca_(V)2.2e[37a] subunits and the compounds and agents so identified. Generally, the screening methods involve assaying for compounds which inhibit or enhance voltage gated calcium influx through human N-type calcium channels. Such methods are adaptable to automated, high throughput screening of compounds. Examples of such methods are described in U.S. Pat. No. 5,429,921.

[0097] A variety of assays for pharmacological agents are provided, including, labeled in vitro protein binding assays, Ca²⁺ influx assays, etc. For example, protein binding screens are used to rapidly examine the binding of candidate pharmacological agents to a Ca_(V)2.2e[37a] polypeptide. The candidate pharmacological agents can be derived from, for example, combinatorial peptide libraries, combinatorial chemical compound libraries, and natural products libraries. Convenient reagents for such assays are known in the art. An exemplary cell-based assay of calcium influx involves contacting a neuronal cell that expresses Ca_(V)2.2e[37a] polypeptides in conjunction with other polypeptides that constitute functional N-type calcium channels with a candidate pharmacological agent under conditions whereby the influx of calcium can be stimulated by application of a voltage to the test system, i.e., by membrane depolarization. Specific conditions are well known in the art and are described in Lin et al., Neuron 18:153-166, 1997, and in U.S. Pat. No. 5,429,921. A reduction in the voltage gated calcium influx in the presence of the candidate pharmacological agent indicates that the candidate pharmacological agent reduces the induction of calcium influx in cells expressing the Ca_(V)2.2e[37a] subunit in response to the voltage stimulus. An increase in the voltage gated calcium influx in the presence of the candidate pharmacological agent indicates that the candidate pharmacological agent increases the induction of calcium influx in cells expressing the Ca_(V)2.2e[37a] subunit in response to the voltage stimulus. Methods for determining changes in the intracellular calcium concentration are known in the art and are described elsewhere herein.

[0098] Ca_(V)2.2e[37a] molecules used in the methods of the invention can be added to an assay mixture as an isolated polypeptide (where binding of a candidate pharmaceutical agent is to be measured) or as a cell or other membrane-encapsulated space which includes a Ca_(V)2.2e[37a] polypeptide. In the latter assay configuration, the cell or other membrane-encapsulated space can contain the Ca_(V)2.2e[37a] molecule as a preloaded polypeptide or as a nucleic acid (e.g. a cell transfected with an expression vector containing a nucleic acid that encodes a Ca_(V)2.2e[37a] polypeptide). In the assays described herein, the Ca_(V)2.2e[37a] polypeptide can be produced recombinantly, or isolated from biological extracts, but preferably is synthesized in vitro. Ca_(V)2.2e[37a] polypeptides encompass chimeric proteins comprising a fusion of a Ca_(V)2.2e[37a] polypeptide with another polypeptide, e.g., a polypeptide capable of providing or enhancing protein-protein binding, or enhancing stability of the Ca_(V)2.2e[37a] polypeptide under assay conditions. A polypeptide fused to a Ca_(V)2.2e[37a] polypeptide or fragment thereof may also provide means of readily detecting the fusion protein, e.g., by immunological recognition or by fluorescent labeling.

[0099] In certain embodiments, the assay includes a control to account for binding and/or modulation of activity of Ca_(V)2.2e[37b] molecules. As above, this can be prepared by expressing a Ca_(V)2.2e[37b] nucleic acid in cells and screening the library of compounds with the cells in parallel with the screening using the Ca_(V)2.2e[37a]-expressing cells. The Ca_(V)2.2e[37b] control cells also can be used to test only positive hit compounds, i.e., those that modulate Ca_(V)2.2e[37a] activity, for their effect on Ca_(V)2.2e[37b] activity. In some instances, the cells can express both Ca_(V)2.2e[37a] and Ca_(V)2.2e[37b] molecules.

[0100] For the cell-based assay described herein, preferred cell types are neurons and other cells that permit expression of N-type calcium channels including Ca_(V)2.2e[37a] molecules, including oocytes as shown in the Examples.

[0101] The assay mixture also comprises a candidate pharmacological agent. Typically, a plurality of assay mixtures are run in parallel with different agent concentrations to obtain a different response to the various concentrations. Typically, one of these concentrations serves as a negative control, i.e., at zero concentration of agent or at a concentration of agent below the limits of assay detection. Candidate agents encompass numerous chemical classes, although typically they are organic compounds. Preferably, the candidate pharmacological agents are small organic compounds, i.e., those having a molecular weight of more than 50 yet less than about 2500. Candidate agents comprise functional chemical groups necessary for structural interactions with polypeptides, and typically include at least an amine, carbonyl, hydroxyl or carboxyl group, preferably at least two of the functional chemical groups and more preferably at least three of the functional chemical groups. The candidate agents can comprise cyclic carbon or heterocyclic structure and/or aromatic or polyaromatic structures substituted with one or more of the above-identified functional groups. Candidate agents also can be biomolecules such as peptides, saccharides, fatty acids, sterols, isoprenoids, purines, pyrimidines, derivatives or structural analogs of the above, or combinations thereof and the like. Where the agent is a nucleic acid, the agent typically is a DNA or RNA molecule, although modified nucleic acids having non-natural bonds or subunits are also contemplated. Thus, antisense and siRNA molecules can be tested for inhibition of Ca_(V)2.2e[37a] expression by these assays and other standard assays of nucleic acid expression, such as PCR. Utilizing the cell-based assays described above allows the identification of antisense and siRNA molecules that inhibit function of Ca_(V)2.2e[37a].

[0102] Candidate agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides, synthetic organic combinatorial libraries, phage display libraries of random peptides, and the like. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. Additionally, natural and synthetically produced libraries and compounds can be readily modified through conventional chemical, physical, and biochemical means. Further, known pharmacological agents may be subjected to directed or random chemical modifications such as acylation, alkylation, esterification, amidification, etc. to produce structural analogs of the agents.

[0103] Candidate agents can be selected randomly or can be based on existing compounds which bind to and/or modulate the function of N-type calcium channels. For example, compounds which are known to inhibit N-type calcium channels include fluspirilene, ziconotide (SNX-111), the ω-conotoxin peptides, as well as small organic molecule calcium channel inhibitors, such as fluspirilene, NNC 09-0026(−)-trans-1-butyl-4-(4-dimethylaminophenyl)-3-[(4-trifluoromethyl-phenoxy) methyl] piperidinedihydrochloride); SB 201823-A (4-[2-(3,4-dichlorophenoxy)ethyl]-1-pentyl piperidinehydrochloride); NS 649 (2-amino-1-(2,5-dimethoxyphenyl)-5-trifluoromethyl benzimidazole); CNS 1237 (N-acenaphthyl-N′-4-methoxynaphth-1-yl guanidine) and riluzole. Therefore, a source of candidate agents are libraries of molecules based on the foregoing N-type calcium channel inhibitors, in which the structure of the inhibitor is changed at one or more positions of the molecule to contain more or fewer chemical moieties or different chemical moieties. The structural changes made to the molecules in creating the libraries of analog inhibitors can be directed, random, or a combination of both directed and random substitutions and/or additions. One of ordinary skill in the art in the preparation of combinatorial libraries can readily prepare such libraries based on the existing N-type calcium channel inhibitors.

[0104] A variety of other reagents also can be included in the mixture. These include reagents such as salts, buffers, neutral proteins (e.g., albumin), detergents, etc. which may be used to facilitate optimal protein-protein and/or protein-nucleic acid binding. Such a reagent may also reduce non-specific or background interactions of the reaction components. Other reagents that improve the efficiency of the assay such as protease inhibitors, nuclease inhibitors, antimicrobial agents, and the like may also be used.

[0105] The mixture of the foregoing assay materials is incubated under conditions whereby, but for the presence of the candidate pharmacological agent, N-type calcium channels containing the Ca_(V)2.2e[37a] subunit transduces a control amount of voltage gated calcium influx. For determining the binding of a candidate pharmaceutical agent to a Ca_(V)2.2e[37a] molecule, the mixture is incubated under conditions which permit binding. The order of addition of components, incubation temperature, time of incubation, and other parameters of the assay may be readily determined. Such experimentation merely involves optimization of the assay parameters, not the fundamental composition of the assay. Incubation temperatures typically are between 4° C. and 40° C. Incubation times preferably are minimized to facilitate rapid, high throughput screening, and typically are between 1 minute and 10 hours.

[0106] After incubation, the level of voltage gated calcium influx or the level of specific binding between the Ca_(V)2.2e[37a] polypeptide and the candidate pharmaceutical agent is detected by any convenient method available to the user. For cell free binding type assays, a separation step is often used to separate bound from unbound components. The separation step may be accomplished in a variety of ways. Conveniently, at least one of the components is immobilized on a solid substrate, from which the unbound components may be easily separated. The solid substrate can be made of a wide variety of materials and in a wide variety of shapes, e.g., microtiter plate, microbead, dipstick, resin particle, etc. The substrate preferably is chosen to maximize signal to noise ratios, primarily to minimize background binding, as well as for ease of separation and cost.

[0107] Separation may be effected for example, by removing a bead or dipstick from a reservoir, emptying or diluting a reservoir such as a microtiter plate well, rinsing a bead, particle, chromatographic column or filter with a wash solution or solvent. The separation step preferably includes multiple rinses or washes. For example, when the solid substrate is a microtiter plate, the wells may be washed several times with a washing solution, which typically includes those components of the incubation mixture that do not participate in specific bindings such as salts, buffer, detergent, non-specific protein, etc. Where the solid substrate is a magnetic bead, the beads may be washed one or more times with a washing solution and isolated using a magnet.

[0108] Detection may be effected in any convenient way for cell-based assays such as a calcium influx assay. The calcium influx resulting from voltage stimulus of a N-type calcium channel containing the Ca_(V)2.2e[37a] polypeptide typically alters a directly or indirectly detectable product, e.g., a calcium sensitive molecule such as fura-2-AM. For cell free binding assays, one of the components usually comprises, or is coupled to, a detectable label. A wide variety of labels can be used, such as those that provide direct detection (e.g., radioactivity, luminescence, optical or electron density, etc). or indirect detection (e.g., epitope tag such as the FLAG epitope, enzyme tag such as horseradish peroxidase, etc.). The label may be bound to a Ca_(V)2.2e[37a] polypeptide or the candidate pharmacological agent.

[0109] A variety of methods may be used to detect the label, depending on the nature of the label and other assay components. For example, the label may be detected while bound to the solid substrate or subsequent to separation from the solid substrate. Labels may be directly detected through optical or electron density, radioactive emissions, nonradiative energy transfers, etc. or indirectly detected with antibody conjugates, streptavidin-biotin conjugates, etc. Methods for detecting the labels are well known in the art.

[0110] Thus the invention provides numerous assays using Ca_(V)2.2e[37a] molecules to identify modulators, preferably inhibitors, of Ca_(V)2.2e[37a] function. In one embodiment the. Ca_(V)2.2e[37a] inhibitor is an antisense oligonucleotide or siRNA molecule that selectively binds to a Ca_(V)2.2e[37a] nucleic acid molecule, to reduce the expression of Ca_(V)2.2e[37a] in a cell. This is desirable in virtually any medical condition wherein a reduction of Ca_(V)2.2e[37a] activity is desirable, e.g., pain.

[0111] As used herein, the term “antisense oligonucleotide” or “antisense” describes an oligonucleotide that is an oligoribonucleotide, oligodeoxyribonucleotide, modified oligoribonucleotide, or modified oligodeoxyribonucleotide which hybridizes under physiological conditions to DNA comprising a particular gene or to an mRNA transcript of that gene and, thereby, inhibits the transcription of that gene and/or the translation of that mRNA. The antisense molecules are designed so as to interfere with transcription or translation of a target gene upon hybridization with the target gene or transcript. Those skilled in the art will recognize that the exact length of the antisense oligonucleotide and its degree of complementarity with its target will depend upon the specific target selected, including the sequence of the target and the particular bases which comprise that sequence.

[0112] As used herein, a “siRNA molecule” is a double stranded RNA molecule (dsRNA) consisting of a sense and an antisense strand, which are complementary (Tuschl, T. et al., 1999, Genes & Dev., 13:3191-3197; Elbashir, S. M. et al., 2001, EMBO J., 20:6877-6888). In one embodiment the last nucleotide at the 3′ end of the antisense strand may be any nucleotide and is not required to be complementary to the region of the target gene. The siRNA molecule may be 19-23 nucleotides in length in some embodiments. In other embodiments, the siRNA is longer but forms a hairpin structure of 19-23 nucleotides in length. In still other embodiments, the siRNA is formed in the cell by digestion of double stranded RNA molecule that is longer than 19-23 nucleotides. The siRNA molecule preferably includes an overhang on one or both ends, preferably a 3′ overhang, and more preferably a two nucleotide 3′ overhang on the sense strand. In another preferred embodiment, the two nucleotide overhang is thymidine-thymidine (TT). The siRNA molecule corresponds to at least a portion of the Ca_(V)2.2e[37a] gene, but preferably a portion that includes or overlaps at least a portion of exon 37. In a preferred embodiment the first nucleotide of the siRNA molecule is a purine. Many variations of siRNA and other double stranded RNA molecules useful for RNAi inhibition of gene expression will be known to one of ordinary skill in the art.

[0113] The siRNA molecules can be plasmid-based. In a preferred method, a polypeptide encoding sequence of Ca_(V)2.2e[37a] is amplified using the well known technique of polymerase chain reaction (PCR). The use of the entire polypeptide encoding sequence is not necessary; as is well known in the art, a portion of the polypeptide encoding sequence is sufficient for RNA interference. For example, the PCR fragment can be inserted into a vector using routine techniques well known to those of skill in the art. The insert can be placed between two promoters oriented in opposite directions, such that two complementary RNA molecules are produced that hybridize to form the siRNA molecule. Alternatively, the siRNA molecule is synthesized as a single RNA molecule that self-hybridizes to form a siRNA duplex, preferably with a non-hybridizing sequence that forms a “loop” between the hybridizing sequences. Preferably the nucleotide encoding sequence is part of the coding sequence of Ca_(V)2.2e[37a], specifically exon 37a to confer specificity. The siRNA can be expressed from a vector introduced into cells.

[0114] Vectors comprising any of the nucleotide coding sequences of the invention are provided for production of siRNA, preferably vectors that include promoters active in mammalian cells. Non-limiting examples of vectors are the pSUPER RNAi series of vectors (Brummelkamp, T. R. et al., 2002, Science, 296:550-553; available commercially from OligoEngine, Inc., Seattle, Wash.). In one embodiment a partially self-complementary nucleotide coding sequence can be inserted into the mammalian vector using restriction sites, creating a stem-loop structure. In a preferred embodiment, the mammalian vector comprises the polymerase-III H1-RNA gene promoter. The polymerase-III H1-RNA promoter produces a RNA transcript lacking a polyadenosine tail and has a well-defined start of transcription and a termination signal consisting of five thymidines (T5) in a row. The cleavage of the transcript at the termination site occurs after the second uridine and yields a transcript resembling the ends of synthetic siRNAs containing two 3′ overhanging T or U nucleotides. Other promoters useful in siRNA vectors will be known to one of ordinary skill in the art.

[0115] Vector systems for siRNA expression in mammalian cells include pSUPER RNAi system described above. Other examples include but are not limited to pSUPER.neo, pSUPER.neo+gfp and pSUPER.puro (OligoEngine, Inc.); BLOCK-iT T7-TOPO linker, pcDNA1.2/V5-GW/lacZ, pENTRIU6, pLenti6-GW/U6-laminshrna and pLenti6/BLOCK-iT-DEST (Invitrogen). These vectors and others are available from commercial suppliers.

[0116] It is preferred that the antisense oligonucleotide or siRNA molecule be constructed and arranged so as to bind selectively with the target under physiological conditions, i.e., to hybridize substantially more to the target sequence than to any other sequence in the target cell under physiological conditions. Based upon sequences encoding Ca_(V)2.2e[37a] polypeptides, or upon allelic or homologous genomic and/or cDNA sequences, one of skill in the art can easily choose and synthesize any of a number of appropriate antisense or siRNA molecules for use in accordance with the present invention. In order to be sufficiently selective and potent for inhibition, such antisense oligonucleotides should comprise at least and, more preferably, at least 15 consecutive bases which are complementary to the target, although in certain cases modified oligonucleotides as short as 7 bases in length have been used successfully as antisense oligonucleotides (Wagner et al., Nature Biotechnol. 14:840-844, 1996). Most preferably, the antisense oligonucleotides comprise a complementary sequence of 20-30 bases. For siRNA molecules, it is preferred that the molecules be 21-23 nucleotides in length, with a 3′ 2 nucleotide overhang, although shorter and longer molecules and molecules without overhangs are also contemplated as usefull in accordance with the inveniton.

[0117] In accordance with the identification of Ca_(V)2.2e[37a] as selectively or preferentially expressed in nociceptive neurons, oligonucleotides useful in selectively reducing expression of Ca_(V)2.2e[37a] are chosen to be complementary to the region of the mRNA transcripts that encode exon 37a for the preparation of antisense or siRNA molecules. In addition, the antisense is targeted, preferably, to sites in which mRNA secondary structure is not expected (see, e.g., Sainio et al., Cell Mol. Neurobiol. 14(5):439-457, 1994) and at which polypeptides are not expected to bind. Other methods for selecting preferred siRNA sequences are known to those of skill in the art (e.g., the “siRNA Selection Program” of the Whitehead Institute for Biomedical Research (2003)).

[0118] In one set of embodiments, the antisense oligonucleotides or siRNA molecules of the invention may be composed of “natural” deoxyribonucleotides, ribonucleotides, or any combination thereof. That is, the 5′ end of one native nucleotide and the 3′ end of another native nucleotide may be covalently linked, as in natural systems, via a phosphodiester internucleoside linkage. These oligonucleotides may be prepared by art recognized methods which may be carried out manually or by an automated synthesizer. They also may be produced recombinantly by vectors, including in situ.

[0119] In preferred embodiments, however, the antisense oligonucleotides or siRNA molecules of the invention also may include “modified” oligonucleotides. That is, the oligonucleotides may be modified in a number of ways which do not prevent them from hybridizing to their target but which enhance their stability or targeting or which otherwise enhance their therapeutic effectiveness.

[0120] The term “modified oligonucleotide” as used herein describes an oligonucleotide in which (1) at least two of its nucleotides are covalently linked via a synthetic internucleoside linkage (i.e., a linkage other than a phosphodiester linkage between the 5′ end of one nucleotide and the 3′ end of another nucleotide) and/or (2) a chemical group not normally associated with nucleic acids has been covalently attached to the oligonucleotide. Preferred synthetic internucleoside linkages are phosphorothioates, alkylphosphonates, phosphorodithioates, phosphate esters, alkylphosphonothioates, phosphoramidates, carbamates, carbonates, phosphate triesters, acetamidates, carboxymethyl esters and peptides.

[0121] The term “modified oligonucleotide” also encompasses oligonucleotides with a covalently modified base and/or sugar. For example, modified oligonucleotides include oligonucleotides having backbone sugars which are covalently attached to low molecular weight organic groups other than a hydroxyl group at the 3′ position and other than a phosphate group at the 5′ position. Thus modified oligonucleotides may include a 2′-O-alkylated ribose group. In addition, modified oligonucleotides may include sugars such as arabinose instead of ribose. The present invention, thus, contemplates pharmaceutical preparations containing modified antisense molecules that are complementary to and hybridizable with, under physiological conditions, nucleic acids encoding Ca_(V)2.2e[37a] polypeptides, together with pharmaceutically acceptable carriers.

[0122] Antisense oligonucleotides or siRNA molecules may be administered as part of a pharmaceutical composition. Such a pharmaceutical composition may include the antisense oligonucleotides or siRNA molecules in combination with any standard pharmaceutically acceptable carriers which are known in the art. The compositions should be sterile and contain a therapeutically effective amount of the antisense oligonucleotides or siRNA molecules in a unit of weight or volume suitable for administration to a patient. The term “pharmaceutically acceptable” means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients. The characteristics of the carrier will depend on the route of administration. Pharmaceutically acceptable carriers include diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials which are well known in the art.

[0123] Agents which bind Ca_(V)2.2e[37a] also include binding peptides which bind to the Ca_(V)2.2e[37a] and complexes containing the Ca_(V)2.2e[37a]. When the binding polypeptides are inhibitors, the polypeptides bind to and inhibit the activity of Ca_(V)2.2e[37a]. To determine whether a Ca_(V)2.2e[37a] binding peptide binds to Ca_(V)2.2e[37a], any known binding assay may be employed. For example, the peptide may be immobilized on a surface and then contacted with a labeled Ca_(V)2.2e[37a] polypeptide. The amount of Ca_(V)2.2e[37a] which interacts with the Ca_(V)2.2e[37a] binding peptide or the amount which does not bind to the Ca_(V)2.2e[37a] binding peptide may then be quantitated to determine whether the Ca_(V)2.2e[37a] binding peptide binds to Ca_(V)2.2e[37a]. Further, the binding of a Ca_(V)2.2e[37a] polypeptide and a Ca_(V)2.2e[37b] peptide can be compared to determine if the binding peptide binds selectively or preferentially.

[0124] The Ca_(V)2.2e[37a] binding peptides include peptides of numerous size and type that bind selectively or preferentially to Ca_(V)2.2e[37a] polypeptides, and complexes of both Ca_(V)2.2e[37a] polypeptides and their binding partners. These peptides may be derived from a variety of sources. For example, Ca_(V)2.2e[37a] binding peptides may include known N-type calcium channel inhibitors such as the ω-conotoxin peptides or modified variants of the foregoing peptides. Binding peptides for Ca_(V)2.2e[37a] polypeptides also can be identified by screening degenerate peptide libraries which can be readily prepared in solution, in immobilized form or as phage display libraries. Combinatorial libraries also can be synthesized of peptides containing one or more amino acids. Libraries further can be synthesized of peptoids and non-peptide synthetic moieties.

[0125] Phage display can be particularly effective in identifying binding peptides useful according to the invention. Briefly, one prepares a phage library (using e.g. m13, fd, or lambda phage), displaying inserts from 4 to about 80 amino acid residues using conventional procedures. The inserts may represent, for example, a completely degenerate or biased array. One then can select phage-bearing inserts which bind to the Ca_(V)2.2e[37a] polypeptide. This process can be repeated through several cycles of reselection of phage that bind to the Ca_(V)2.2e[37a] polypeptide. Repeated rounds lead to enrichment of phage bearing particular sequences. DNA sequence analysis can be conducted to identify the sequences of the expressed polypeptides. The minimal linear portion of the sequence that binds to the Ca_(V)2.2e[37a] polypeptide can be determined. One can repeat the procedure using a biased library containing inserts containing part or all of the minimal linear portion plus one or more additional degenerate residues upstream or downstream thereof. Yeast two-hybrid screening methods also may be used to identify polypeptides that bind to the Ca_(V)2.2e[37a] polypeptides. Thus, the Ca_(V)2.2e[37a] polypeptides of the invention, or a fragment thereof, can be used to screen peptide libraries, including phage display libraries, to identify and select peptide binding partners of the Ca_(V)2.2e[37a] polypeptides of the invention. Such molecules can be used as described, for screening assays, for purification protocols, for interfering directly with the functioning of Ca_(V)2.2e[37a] and for other purposes that will be apparent to those of ordinary skill in the art.

[0126] Peptides may easily be synthesized or produced by recombinant means by those of skill in the art. Using routine procedures known to those of ordinary skill in the art, one can determine whether a peptide which binds to Ca_(V)2.2e[37a] is useful according to the invention by determining whether the peptide is one which inhibits the activity of Ca_(V)2.2e[37a] such as in a voltage gated calcium influx assay, as discussed herein.

[0127] The Ca_(V)2.2e[37a] binding peptide agent may also be an antibody or a functionally active antibody fragment. Antibodies are well known to those of ordinary skill in the science of immunology. As used herein, the term “antibody” means not only intact antibody molecules but also fragments of antibody molecules retaining Ca_(V)2.2e[37a] binding ability (antigen binding fragments). Such fragments are also well known in the art and are regularly employed both in vitro and in vivo. In particular, as used herein, the term “antibody” means not only intact immunoglobulin molecules but also well-known active fragments such as F(ab′)₂ and Fab and Fv (including single chain antibodies).

[0128] An antibody refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system.

[0129] The term “antigen-binding fragment” of an antibody as used herein, refers to one or more portions of an antibody that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term “antigen-binding fragment” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab′)₂ fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546) which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term “antigen-binding fragment” of an antibody. These antibody fragments are obtained using conventional procedures, such as proteolytic fragmentation procedures, as described in J. Goding, Monoclonal Antibodies: Principles and Practice, pp 98-118 (N.Y. Academic Press 1983), which is hereby incorporated by reference as well as by other techniques known to those with skill in the art. The fragments are screened for utility in the same manner as are intact antibodies.

[0130] An “isolated antibody”, as used herein, is intended to refer to an antibody which is substantially free of other antibodies having different antigenic specificities (e.g., a population of isolated antibodies that specifically binds to Ca_(V)2.2e[37a], is substantially free of antibodies that specifically bind antigens other than a Ca_(V)2.2e[37a] molecule). An isolated antibody that specifically binds to an epitope, isoform or variant of Ca_(V)2.2e[37a] may, however, have cross-reactivity to other related antigens, e.g., from other species (e.g., species homologs). Moreover, an isolated antibody may be substantially free of other cellular material and/or chemicals. As used herein, “specific binding” refers to antibody binding to a predetermined antigen. Typically, the antibody binds Ca_(V)2.2e[37a] or a closely-related antigen with an affinity that is at least two-fold greater than its affinity for binding to a non-specific antigen (e.g., BSA, casein) or Ca_(V)2.2e[37b].

[0131] The isolated antibodies of the invention encompass various antibody isotypes, such as IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD, IgE. As used herein, “isotype” refers to the antibody class (e.g. IgM or IgG1) that is encoded by heavy chain constant region genes. The antibodies can be full length or can include only an antigen-binding fragment such as the antibody constant and/or variable domain of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD or IgE or could consist of a Fab fragment, a F(ab′)₂ fragment, and a Fv fragment.

[0132] As used herein, antibodies also include single chain antibodies (e.g., scFvs). In some embodiments, the single chain antibodies are disulfide-free antibodies having mutations e.g., in disulfide bond forming cysteine residues. The antibodies may be prepared by starting with any of a variety of methods, including administering Ca_(V)2.2e[37a]protein, fragments of Ca_(V)2.2e[37a] protein that include SEQ ID NO:45, cells expressing the protein or fragments thereof and the like to an animal to induce polyclonal antibodies. Such antibodies or antigen-binding fragments thereof may be used in the preparation of scFvs and disulfide-free variants thereof. The antibodies or antigen-binding fragments thereof may be used for example to modulate the activity of a target protein (e.g. Ca_(V)2.2e[37a]).

[0133] Various forms of the antibody polypeptide or encoding nucleic acid can be administered and delivered to a mammalian cell (e.g., by virus or liposomes, or by any other suitable methods known in the art). The method of delivery can be modified to target certain cells, and in particular, cell surface receptor molecules or antigens present on specific cell types. Methods of targeting cells to deliver nucleic acid constructs, for intracellular expression of the antibodies, are known in the art. The antibody polypeptide sequence can also be delivered into cells by expressing a recombinant protein fused with peptide carrier molecules. These carrier molecules, which are also referred to herein as protein transduction domains (PTDs), and methods for their use, are known in the art. Examples of PTDs, though not intended to be limiting, are tat, antennapedia, and synthetic poly-arginine. These delivery methods are known to those of skill in the art and are described in U.S. Pat. No. 6,080,724, and U.S. Pat. No. 5,783,662, the entire contents of which are hereby incorporated by reference.

[0134] The antibodies of the present invention can be polyclonal, monoclonal, or a mixture of polyclonal and monoclonal antibodies. The antibodies can be produced by a variety of techniques well known in the art. Procedures for raising polyclonal antibodies are well known and are disclosed for example in E. Harlow, et. al., editors, Antibodies: A Laboratory Manual (1988), which is hereby incorporated by reference.

[0135] Monoclonal antibody production may be effected by techniques which are also well known in the art. The term “monoclonal antibody,” as used herein, refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody displays a single binding specificity and affinity for a particular epitope. The process of monoclonal antibody production involves obtaining immune somatic cells with the potential for producing antibody, in particular B lymphocytes, which have been previously immunized with the antigen of interest either in vivo or in vitro and that are suitable for fusion with a B-cell myeloma line.

[0136] Mammalian lymphocytes typically are immunized by in vivo immunization of the animal (e.g., a mouse) with the desired protein or polypeptide, e.g., with a Ca_(V)2.2e[37a] polypeptide. Such immunizations are repeated as necessary at intervals of up to several weeks to obtain a sufficient titer of antibodies. Once immunized, animals can be used as a source of antibody-producing lymphocytes. Following the last antigen boost, the animals are sacrificed and spleen cells removed. See; Goding (in Monoclonal Antibodies: Principles and Practice, 2d ed., pp. 60-61, Orlando, Fla., Academic Press, 1986).

[0137] The antibody-secreting lymphocytes are then fused with (mouse) B cell myeloma cells or transformed cells, which are capable of replicating indefinitely in cell culture, thereby producing an immortal, immunoglobulin-secreting cell line. The resulting fused cells, or hybridomas, are cultured, and the resulting colonies screened for the production of the desired monoclonal antibodies. Colonies producing such antibodies are cloned, and grown either in vivo or in vitro to produce large quantities of antibody. A description of the theoretical basis and practical methodology of fusing such cells is set forth in Kohler and Milstein, Nature 256:495 (1975), which is hereby incorporated by reference.

[0138] Myeloma cell lines suited for use in hybridoma-producing fusion procedures preferably are non-antibody-producing, have high fusion efficiency, and enzyme deficiencies that render them incapable of growing in certain selective media which support the growth of the desired hybridomas. Examples of such myeloma cell lines that may be used for the production of fused cell lines include P3-X63/Ag8, X63-Ag8.653, NS1/1.Ag 4.1, Sp2/0-Ag14, FO, NSO/U, MPC-11, MPC11-X45-GTG 1.7, S194/5XX0 Bul, all derived from mice; R210.RCY3, Y3-Ag 1.2.3, IR983F and 4B210 derived from rats and U-266, GM1500-GRG2, LICR-LON-HMy2, UC729-6, all derived from humans (Goding, in Monoclonal Antibodies: Principles and Practice, 2d ed., pp. 65-66, Orlando, Fla., Academic Press, 1986; Campbell, in Monoclonal Antibody Technology, Laboratory Techniques in Biochemistry and Molecular Biology Vol. 13, Burden and Von Knippenberg, eds. pp. 75-83, Amsterdam, Elseview, 1984).

[0139] Fusion with mammalian myeloma cells or other fusion partners capable of replicating indefinitely in cell culture is effected by standard and well-known techniques, for example, by using polyethylene glycol (“PEG”) or other fusing agents (See Milstein and Kohler, Eur. J. Immunol. 6:511 (1976), which is hereby incorporated by reference).

[0140] In other embodiments, the antibodies can be recombinant antibodies. The term “recombinant antibody”, as used herein, is intended to include antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from an animal (e.g., a mouse) that is transgenic for another species' immunoglobulin genes, antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant, combinatorial antibody library, or antibodies prepared, expressed, created or isolated by any other means that involves splicing of immunoglobulin gene sequences to other DNA sequences.

[0141] In yet other embodiments, the antibodies can be chimeric or humanized antibodies. As used herein, the term “chimeric antibody” refers to an antibody, that combines the murine variable or hypervariable regions with the human constant region or constant and variable framework regions. As used herein, the term “humanized antibody” refers to an antibody that retains only the antigen-binding CDRs from the parent antibody in association with human framework regions (see, Waldmann, 1991, Science 252:1657). Such chimeric or humanized antibodies retaining binding specificity of the murine antibody are expected to have reduced immunogenicity when administered in vivo for diagnostic, prophylactic or therapeutic applications according to the invention.

[0142] In certain embodiments, the antibodies are human antibodies. The term “human antibody”, as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term “human antibody”, as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse have been grafted onto human framework sequences (referred to herein as “humanized antibodies”). Fully human monoclonal antibodies also can be prepared by immunizing mice transgenic for large portions of human immunoglobulin heavy and light chain loci. See, e.g., U.S. Pat. Nos. 5,591,669, 5,598,369, 5,545,806, 5,545,807, 6,150,584, and references cited therein, the contents of which are incorporated herein by reference. These animals have been genetically modified such that there is a functional deletion in the production of endogenous (e.g., murine) antibodies. The animals are further modified to contain all or a portion of the human germ-line immunoglobulin gene locus such that immunization of these animals results in the production of fully human antibodies to the antigen of interest. Following immunization of these mice (e.g., XenoMouse (Abgenix), HuMAb mice (Medarex/GenPharm)), monoclonal antibodies are prepared according to standard hybridoma technology. These monoclonal antibodies have human immunoglobulin amino acid sequences and therefore will not provoke human anti-mouse antibody (HAMA) responses when administered to humans. In particular, mouse strains that have human immunoglobulin genes inserted in the genome (and which cannot produce mouse immunoglobulins) are preferred. Such mice produce fully human immunoglobulin molecules in response to immunization.

[0143] According to the invention Ca_(V)2.2e[37a] inhibitors also include “dominant negative” polypeptides. A dominant negative polypeptide is an inactive variant of a polypeptide, which, by interacting with the cellular machinery, displaces an active polypeptide from its interaction with the cellular machinery or competes with the active polypeptide, thereby reducing the effect of the active polypeptide. For example, a dominant negative Ca_(V)2.2e[37a] subunit of an active complex (e.g. N-type calcium channel) can interact with the complex but prevent the activity of the complex (e.g., voltage gated calcium influx).

[0144] Alternatively, non-human transgenic animal can be prepared using the Ca_(V)2.2e[37a] nucleic acid described herein. A “transgenic animal” is an animal having cells that contain DNA which has been artificially inserted into a cell, which DNA becomes part of the genome of the animal which develops from that cell, or which contain nucleic acid molecules that are expressed in a cell transiently. Preferred transgenic animals are primates, mice, rats, cows, pigs, horses, goats, sheep, dogs and cats. A variety of methods for the production of transgenic animals are well known in the art. Animals suitable for transgenic experiments can be obtained from standard commercial sources such as Charles River (Wilmington, Mass.), Taconic (Germantown, N.Y.), Harlan Sprague Dawley (Indianapolis, Ind.), etc. Transgenic animals having a particular property associated with a particular disease can be used to study the affects of a variety of drugs and treatment methods on the disease, and thus serve as genetic models for the study of a number of human diseases. The invention, therefore, contemplates the use of Ca_(V)2.2e[37a] transgenic animals as models for the study of disorders involving voltage gated calcium influx in nociceptive neurons.

[0145] Inactivation or replacement of exon 37a of the endogenous Ca_(V)2.2 subunit gene can be achieved, for example, by a homologous recombination system using embryonic stem cells. The resultant transgenic non-human mammals (preferably primates) having a knockout Ca_(V)2.2e[37a] characteristic may be used as a model for the effects of compounds that selectively or preferentially inhibit Ca_(V)2.2e[37a] activity. A similar effect can be achieved by testing the antisense or siRNA molecules described herein in order to prepare “knockdown” animals in which expression of Ca_(V)2.2e[37a] is reduced or eliminated. Such animals also can be used to assess the effects of antisense or siRNA therapies.

[0146] The compositions of the invention are also useful for therapeutic purposes. Accordingly the invention encompasses a method for modulating (reducing or increasing) Ca_(V)2.2e[37a] activity in a mammalian cell. In preferred embodiments, the method involves contacting the mammalian cell with an amount of a Ca_(V)2.2e[37a] inhibitor effective to inhibit voltage gated calcium influx in the mammalian cell. Such methods are useful in vitro for altering voltage gated calcium influx for the purpose of, for example, elucidating the mechanisms involved in pain, e.g., neuropathic pain, and for restoring normal voltage gated calcium influx in a cell having a defective (excessively active) Ca_(V)2.2e[37a]. In vivo, such methods are useful, for example, for reducing N-type voltage gated calcium influx, e.g., to treat pain, e.g., neuropathic pain, or any condition in which Ca_(V)2.2e[37a] activity is elevated.

[0147] An amount of a Ca_(V)2.2e[37a] inhibitor which is effective to inhibit voltage gated calcium influx in the mammalian cell is an amount which is sufficient to reduce voltage gated calcium influx by at least 10%, preferably at least 20%, more preferably 30% and still more preferably 40%. An amount of a Ca_(V)2.2e[37a] which is effective to increase voltage gated calcium influx in the mammalian cell is an amount which is sufficient to increase voltage gated calcium influx by at least 10%, preferably at least 20%, more preferably 30% and still more preferably 40%. Such alterations in voltage gated calcium influx can be measured by the assays described herein.

[0148] As described above with respect to inhibitors, modulators of Ca_(V)2.2e[37a] may selectively or preferentially inhibit or increase Ca_(V)2.2e[37a] function based on the state of depolarization of the membrane with which the Ca_(V)2.2e[37a] polypeptide is associated. Therefore, in screening for modulators of Ca_(V)2.2e[37a], it is preferred that compounds (e.g. synthetic combinatorial libraries, natural products, peptide libraries, etc.) are tested for modulation of Ca_(V)2.2e[37a] activity at a variety of voltages which cause partial or complete membrane depolarization, or hyperpolarization. These assays are conducted according to standard procedures of testing calcium channel function (e.g. patch clamping, fluorescent Ca²⁺ influx assays) which require no more than routine experimentation. Using such methods, modulators of Ca_(V)2.2e[37a] activity which are active at particular voltages (e.g. complete membrane depolarization) can be identified. Such compounds are useful for selectively modulating calcium channel activity in conditions which may display voltage dependence.

[0149] The invention also encompasses a method for increasing Ca_(V)2.2e[37a] expression in a cell. It is desirable to increase Ca_(V)2.2e[37a] in a cell, for example, to prepare cells useful in the assays described herein. The amount of Ca_(V)2.2e[37a] can be increased in such cell by contacting the cell with a Ca_(V)2.2e[37a] nucleic acid or a Ca_(V)2.2e[37a] polypeptide of the invention in an amount effective to increase voltage gated calcium influx in the cell. An increase in Ca_(V)2.2e[37a] activity can be measured by the assays described herein, e.g., assays of calcium influx.

[0150] The preparations of the invention are administered in effective amounts. An effective amount is that amount of a pharmaceutical preparation that alone, or together with further doses, produces the desired response. In the case of treating a condition characterized by aberrant voltage gated calcium influx, the desired response is reducing or increasing calcium influx to a level which is within a normal range. Preferably, the change in calcium influx produces a detectable reduction in a physiological function related to the condition, e.g., a reduction in pain. The responses can be monitored by routine methods. In the case of a condition where an increase in voltage gated calcium influx is desired, an effective amount is that amount necessary to increase said influx in the target tissue. The converse is the case when a reduction in influx is desired. When administered for treatment of pain conditions, the effectiveness of inhibitors of Ca_(V)2.2e[37a] can be assessed directly by querying the patient regarding, e.g., the extent and duration of pain relief.

[0151] Such amounts will depend, of course, on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.

[0152] Generally, doses of active compounds would be from about 0.01 ng/kg per day to 1000 mg/kg per day. It is expected that doses ranging from 50 g-500 mg/kg will be suitable and in one or several administrations per day. Lower doses can result from other forms of administration, such as intravenous administration. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of compound, although fewer doses typically will be given when compounds are prepared as slow release or sustained release medications.

[0153] When administered, the pharmaceutical preparations of the invention are applied in pharmaceutically-acceptable amounts and in pharmaceutically-acceptably compositions. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents. When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically-acceptable salts thereof and are not excluded from the scope of the invention. Such pharmacologically and pharmaceutically-acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like. Also, pharmaceutically-acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.

[0154] The Ca_(V)2.2e[37a] inhibitors or Ca_(V)2.2e[37a] nucleic acids and polypeptides useful according to the invention may be combined, optionally, with a pharmaceutically-acceptable carrier. The term “pharmaceutically-acceptable carrier” as used herein means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration into a human. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being co-mingled with the molecules of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.

[0155] The pharmaceutical compositions may contain suitable buffering agents, including: acetic acid in a salt; citric acid in a salt; and phosphoric acid in a salt.

[0156] The pharmaceutical compositions also may contain, optionally, suitable preservatives, such as: benzalkonium chloride; chlorobutanol; parabens and thimerosal.

[0157] A variety of administration routes are available. The particular mode selected will depend, of course, upon the particular compound selected, the severity of the condition being treated and the dosage required for therapeutic efficacy. The methods of the invention, generally speaking, may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects. Such modes of administration include oral, rectal, topical, nasal, interdermal, or parenteral routes. The term “parenteral” includes subcutaneous, intravenous, intrathecal, intramuscular, or infusion.

[0158] The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacy. All methods include the step of bringing the active agent into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0159] Compositions suitable for oral administration may be presented as discrete units, such as capsules, tablets, lozenges, each containing a predetermined amount of the active compound. Other compositions include suspensions in aqueous liquids or non-aqueous liquids such as a syrup, elixir or an emulsion.

[0160] Compositions suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the Ca_(V)2.2e[37a] inhibitor or Ca_(V)2.2e[37a] nucleic acids and polypeptides, which is preferably isotonic with the blood of the recipient. This aqueous preparation may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation also may be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or di-glycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables. Carrier formulation suitable for oral, subcutaneous, intravenous, intrathecal, intramuscular, etc. administrations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.

[0161] Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the active compound, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. Use of a long-term sustained release implant may be desirable. Long-term release, are used herein, means that the implant is constructed and arranged to delivery therapeutic levels of the active ingredient for at least 30 days, and preferably 60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.

[0162] The invention will be more fully understood by reference to the following examples. These examples, however, are merely intended to illustrate the embodiments of the invention and are not to be construed to limit the scope of the invention.

EXAMPLES Example 1 Analysis of N-type Calcium Current and Ca_(V)2.2a1 Splice Variants in Nociceptive Neurons

[0163] N-type calcium channels are important for pain transduction. The N-type Ca_(V)2.2 α1 gene contains a number of exons that are subject to tissue-specific alternative splicing (Lipscombe et al., 2002). Dorsal root ganglia (DRG) neurons express multiple Ca_(V)2.2 α1 splice isoforms (Bell et al., 2001). Here we report that exon 37a (e37a), located in the C-terminus of Ca_(V)2.2 α1, is expressed in a subset of nociceptive neurons. E37a encodes 32 amino acids in the C-terminus, is expressed in a mutually exclusive manner with e37b, and disrupts a putative EF-hand motif. The cell-specific expression of e37a prompted us to compare the functional properties of N-type calcium channel currents in dorsal root ganglia. Nociceptive neurons express signature markers such as the non-specific cation channel VR-1 (Caterina et al., 1997). DRG neurons were therefore operationally defined as nociceptive if they responded to the VR-1 receptor ligand capsaicin. We found that capsaicin-responsive neurons containing e37a have a statistically greater peak N-type current density compared to capsaicin-responsive neurons that lack e37a.

[0164] Materials and Methods

[0165] Calcium Current Recordings

[0166] Acutely dissociated DRG neurons were placed into the recording chamber containing Tyrodes solution (140 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 0.5 mM MgCl₂, 10 mM HEPES, and 15 mM Dextrose; the pH was adjusted to 7.2 with NaOH). Patch electrodes were fabricated from borosilicate glass and polished to a resistance of 1-2 MΩ. The internal solution for the perforated patch recordings consisted of 135 mM CsCl, 10 mM HEPES, 1 mM EGTA, 1 mM EDTA, 4 mM MgCl₂ 1.2 pg/ml amphotericin and adjusted to a pH of 7.2 with TEA-OH. Seals were formed in Tyrodes solution. The series resistance decreased over a 20 min period and deemed acceptable when it fell below 12 MΩ. The bath solution was then replaced with 135 mM TEA-Cl, 2 mM CaCl₂, 10 mM HEPES, 100 nM TTX and adjusted to a pH of 7.2 with TEA-OH. Whole cell calcium currents were recorded under constant bath perfusion. A current voltage protocol from a holding potential of −80 mV with 50 ms test pulses was then delivered. ω-Ctx GVIA (3 μM) was then applied via a second pipette using positive pressure. Test pulses at 20 second intervals were applied during toxin application. When toxin block was maximal (three test pulses generating equal sized currents) a second current voltage protocol was delivered. Finally the bath solution was exchanged with Tyrodes and the cell was held at −60 mV. 2 μM capsaicin in Tyrodes was then exposed to the cell. The entire cell was then harvested and stored in first-strand buffer at −80 until needed. After each application of ω-Ctx GVIA, the recording chamber was soaked in 2% SDS and 10 mM DTT for 15 min to remove any residual ω-Ctx GVIA. Data acquisition was performed using pClamp V8.1 software and the Axopatch 200A (Axon Instruments). For recordings of calcium current data was filtered at 2 kHz and sampled at 20 kHz. The series resistance was compensated by 70-90% with a 10 ms lag. Leak correction was performed with a p/−4 protocol. For recordings of VR-1 current data was filtered at 2 kHz and sampled at 2 kHz. No leak subtraction or series resistance compensation was performed. All recordings were obtained at room temperature.

[0167] Capsaicin Screening

[0168] Viable neurons were identified using whole cell voltage clamp recordings based on the presence of robust voltage-gated sodium and potassium currents. Neurons were then exposed to 2 μM capsaicin (Sigma). After exposure, the bath was washed and the cell allowed to recover. Capsaicin-responsive cells had to recover after wash to be included. Capsaicin-non-responsive neurons were expose at least twice to capsaicin before the cell was collected and counted as capsaicin-non-responsive. Coverslips in the study were limited to two exposures of capsaicin to avoid desensitization. 1-2 MΩ microelectrodes were filled with an internal solution consisting of 90 mM KCl, 10 mM NaCl, 5 mM MgCl₂, 40 mM HEPES, 5 mM EGTA and the pH was adjusted to 7.4 with KOH. The bath solution contained 140 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 0.5 mM MgCl₂, 10 mM HEPES, and 15 mM Dextrose. The pH was adjusted to 7.2 with NaOH. At the conclusion of the recording the entire cell was harvested via the recording pipette by negative pressure and stored in first-strand buffer at −80° C. until needed. Data acquisition was performed using PClamp V8.1 software and Axopatch 200A (Axon Instruments). Data was filtered at 2 kHz and sampled at 2 kHz. No leak correction or series resistance compensation was performed. The recordings were obtained at room temperature.

[0169] Single Cell RT-PCR Protocol

[0170] The electrode tip and its contents (˜2 μl) were broken into a thin-walled PCR tube containing water and First-strand buffer cDNA was synthesized from single cells according the Superscript II protocol with minor modifications. cDNA from single cells was then used as a template for subsequent PCR reactions with primers for GAPDH (0.1 of cDNA) and Ca_(V)2.2 α1 e37a or e37b (˜0.5 of cDNA). Products were then run out on 2% standard agarose and stained with EthBr. Competitive PCR templates were spiked into PCR reactions for either e37a and e37b. For 1 ng DRG tissue (˜10 cells) competitor dilutions of 10⁻¹⁸-10⁻²² and for single cell cDNA 10-20 were used. Products were then run out on 4% Metaphor agarose gels and stained with EthBr. Band intensities were directly quantified from gels using a digital analysis system (Alpha Innotech).

[0171] Results

[0172]FIG. 1 shows RT-PCR analysis of e37a and e37b splice variants. RT-PCR analysis of e37a and e37b splice variants of Ca_(V)2.2 from rat dorsal root ganglia showed that Ca_(V)2.2 containing exons 37a or e37b were expressed in rat DRG tissue (P5).

[0173]FIG. 2 shows RT-PCR analysis of e37a and e37b in single DRG neurons. The PCR primer pairs were exon-specific for e37a and e37b. The predicted PCR product was 108 bp for both e37a and e37b. FIG. 2A, Representative gel for scRT-PCR for e37a, e37b and GAPDH in the same neuron. FIG. 2B, Diagrams of the PCR primer locations for each site.

[0174]FIG. 3 shows single cell RT-PCR (scRT-PCR) analysis of Ca_(V)2.2 e37a and e37b in capsaicin-responsive and capsaicin-non-responsive neurons. FIG. 3A, Representative gel for scRT-PCR for e37a and GAPDH. FIG. 3B, Representative gel for scRT-PCR for e37b and GAPDH. FIG. 3C, Bar graph summary of e37a and e37b results.

[0175] Exon 37a was expressed only in a subset of neurons. e37a PCR products were detected in 55% of capsaicin-responsive neurons (32 of 58) but in only 19% (5 of 27) of non-responsive neurons. This result suggests that exon 37a is expressed in a subset of nociceptive neurons in the DRG.

[0176]FIG. 4 shows the experimental protocol for certain experiments. DRG neurons from P5-8 rats were dissociated and immediately plated on glass coverslips. FIG. 4A, Whole cell voltage-clamp recordings of calcium currents were performed using the perforated patch technique. Current-voltage curves were obtained from each cell (holding potential=−80 mV). FIG. 4B, 3 mM ω-Ctx GVIA was then applied via a micropipette and the onset of block assessed by test pulses to peak current every 20 seconds. At maximum block a second I-V curve was obtained. FIG. 4C, Post-toxin currents were digitally subtracted from pre-toxin currents to reveal the toxin-sensitive component of the whole cell calcium current. FIG. 4D, Finally, 2 mM capsaicin was applied and the presence of an inward current of at least 25 pA at a holding potential of −60 mV, defined a capsaicin-responsive neuron. FIG. 4E, Neurons were collected for single cell RT-PCR analysis of e37a and 37b of Ca_(V)2.2, and GAPDH.

[0177]FIG. 5 shows whole cell calcium currents in capsaicin-responsive and capsaicin-non-responsive neurons. FIG. 5A, I-V plots of the whole cell calcium current in capsaicin-responsive (∘) and capsaicin-non-responsive (▪) DRG neurons. FIG. 5B, Representative low voltage-activated (LVA) and high voltage-activated (HVA) whole cell calcium currents from a capsaicin-non-responsive neuron. FIG. 5C, Same as FIG. 5B from a capsaicin-responsive neuron. FIG. 5D, Summary of peak calcium current density and capacitance of capsaicin-responsive (V_(1/2)˜−˜15 mV) and non-responsive neurons (V_(1/2)˜−45 mV and −15 mV for LVA and HVA, respectively. The whole cell capacitance of capsaicin-non-responsive neurons is significantly greater compared to capsaicin-responsive neurons (Students t test; p<0.001).

[0178]FIG. 6 shows that ω-Ctx GVIA-sensitive calcium currents in capsaicin-responsive and capsaicin-non-responsive neurons. FIG. 6A, I-V plots of ω-Ctx GVIA-sensitive calcium current in capsaicin-responsive (∘) and capsaicin-non-responsive (▪) DRG neurons. V_(1/2)=−15 mV for capsaicin-responsive and V_(1/2)=˜−45 mV and −15 mV for LVA and HVA currents in capsaicin-non-responsive neurons. FIG. 6B, Representative ω-Ctx GVIA-sensitive calcium currents. FIG. 6C, Summary of peak calcium channel current density, % ω-Ctx GVIA-sensitive calcium current, and capacitance in capsaicin-responsive and non-responsive neurons.

[0179]FIG. 7 shows that LVA currents rundown significantly over a 5 minute time period in capsaicin-non-responsive neurons. The presence of a low voltage-activated GVIA-sensitive current in capsaicin-non-responsive cells is surprising (FIG. 6A). GVIA is well known for is selective effects on N-type HVA currents. We therefore tested the hypothesis that the LVA current ran down over the time period of the experiment even in the absence of GVIA. The same voltage protocol used during the toxin application experiments was employed. Only 52±2% of the LVA current (−40 mV) remained after 5 minutes compared to 89±1% of HVA current (−10 mV). The apparent presence of GVIA-sensitive LVA currents in capsaicin-non-responsive neurons in FIG. 6 is simply a function of preferential rundown of LVA currents.

[0180]FIG. 8 shows ω-Ctx GVIA-sensitive calcium currents in capsaicin-responsive neurons that contain and lack e37a. FIG. 8A, I-V plots of ω-Ctx GVIA-sensitive calcium currents in capsaicin-responsive neurons that contain (∘) and lack (▪) e37a. FIG. 8B, Representative gel from scRT-PCR for e37a, e37b, and GAPDH in the same neuron. PCR primer locations are shown. FIG. 8C, Summary of GVIA-sensitive peak calcium current density, % ω-Ctx GVIA-sensitive calcium current, and capacitance in capsaicin-responsive and non-responsive neurons. The peak N-type current density was significantly greater in capsaicin-responsive neurons containing e37a compared to exon 37a-lacking (Students t test; p<0.05). V_(1/2)˜−15 mV for both groups.

[0181]FIG. 9 shows competitive RT-PCR analysis of e37a and e37b in whole tissue and single neurons. Using different exon-specific PCR primers for e37a and e37b, we were not able to determine relative levels of each exon. To estimate approximate levels of e37a and e37b we used a competitive single cell RT-PCR protocol. Each primers pair generated two PCR products; a 108 bp product from endogenous Ca_(V)2.2 cDNA and a 135 bp product from the competitive template added in known amounts to PCR reactions. FIG. 9A, Representative gel for RT-PCR of whole DRG tissue for e37a and e37b in the presence of serial dilutions of competitive template (10⁻¹⁸-10⁻²² M). FIG. 9B, Representative gel for scRT-PCR for e37a and e37b with the same competitive template dilution (10⁻²⁰ M) from the same neuron.

SUMMARY

[0182] Exon 37a of Ca_(V)2.2α1 is restricted to a subset of DRG neurons. 55% of capsaicin-responsive neurons expressed e37a while only 19% of capsaicin-non-responsive neurons e37a.

[0183] Analysis of whole cell calcium current revealed that capsaicin-non-responsive neurons express a low voltage-activating current that is less prominent in capsaicin-responsive neurons. The N-type current density was slightly, but not significantly greater in capsaicin-responsive (108±13 pA/pF) compared to non-responsive neurons (77±9 pA/pF)

[0184] Capsaicin-responsive neurons that contain e37a have a significantly larger N-type current (108±16 pA/pF) compared to capsaicin-responsive neurons that lack e37a (65±4 pA/pF). Students t test; p<0.05).

[0185] Conclusions

[0186] We have demonstrated that Ca_(V)2.2α1 splice variants containing e37a are preferentially expressed in a subset of nociceptive neurons of the dorsal root ganglia.

[0187] The functional significance of exon 37a is not yet known, however, capsaicin-responsive neurons that contain e37a have a larger N-type current compared to those lacking e37a.

[0188] It is possible that e37a promotes surface expression of Ca_(V)2.2. The greater N current density in nociceptive neurons expressing e37a may have significance specific to the physiology of pain.

Example 2 Cell-Specific Alternative Splicing Increases Calcium Channel Current Density in the Pain Pathway

[0189] Experimental Procedures

[0190] Whole Tissue RT-PCR

[0191] Total RNA was isolated from various parts of the rat nervous system with Trizol reagent (Invitrogen, Carlsbad, Calif.). 2 μg of total RNA from each tissue was reverse transcribed with Superscript II (Invitrogen). 10 ng of the first strand cDNA mixture was analyzed using the Advantage 2 PCR system (BD Biosciences). PCR products were cloned and sequenced to confirm their molecular identity. RT-PCR primers for e37a were: rat37a-up, 5′gctgcgtgttgccggattcattat (SEQ ID NO:1); rat37a-dw, 5′ttcattcgaaccaggcgcttgtag (SEQ ID NO:2) (122 bp) and for e37b: rat37b-up, 5′ctgaatacgacccagctgcgtgtg (SEQ ID NO:3); rat37b-dw,5′ccaggcgcttgtatgcaactcgag (SEQ ID NO:4) (126 bp). PCR was performed using a Robocycler (Stratagene) programmed as follows: 1 cycle of 94° C. for 1 min; followed by 30 cycles of 94° C. for 30 sec, 59° C. for 30 sec, and 72° C. for 30 sec; followed by a final 7 min extension at 72° C. Control amplifications were performed with cDNAs to ensure the primers were specific for e37a and e37b. RT-PCR products were run on 3% agarose gels pre-stained with ethidium bromide and imaged on a digital analysis system (Alpha Innotech, San Leandro, Calif.).

[0192] Cell Isolation

[0193] Dorsal root ganglia were harvested from all spinal levels of P5 to P8 rats (Sprague Dawley, Charles River, Wilmington, Mass.). Ganglia were dissociated in a solution containing supplemented L-15 media with collagenase (20 mg/ml, Sigma Chemical Co., St. Louis, Mo.) and dispase (96 mg/ml, Sigma). Enzymatic digestion was carried out at 37° C. for 45 min and cells triturated periodically with a fire polished pipette to facilitate dissociation. Neurons were washed twice in 1×PBS (Gibco Invitrogen) and plated on poly-D-lysine (Sigma) coated covers slips in DMEM (Gibco) containing 10% FBS (Gibco) and NGF (1 ng/ml, Sigma). Neurons were maintained at 37° C. with 5% CO₂ and used within 1 to 6 hrs after isolation.

[0194] Capsaicin Screening

[0195] Viable neurons were identified by the presence of robust voltage-gated sodium and potassium currents during brief depolarizations from a holding potential of −80 mV. Cells were then maintained at a holding potential of −60 mV and challenged with 2 μM capsaicin to identify responsive and non-responsive neurons. Neurons were then washed with capsaicin-free media. For inclusion in the analysis, capsaicin-induced inward currents had to be at least 25 pA and recover after capsaicin removal. Capsaicin induced currents ranged from 25 pA to 4500 pA. Capsaicin-non-responsive neurons were exposed to capsaicin at least twice before the cell was harvested and counted as capsaicin-non-responsive. Neurons were limited to two exposures of capsaicin to avoid desensitization. For capsaicin screening, currents were recorded using 1-2 MΩ microelectrodes filled with an internal solution consisting of 90 mM KCl, 10 mM NaCl, 5 mM MgCl₂ 40 mM HEPES, and 5 mM EGTA adjusted to a pH of 7.4 with KOH. The bath solution contained 140 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 0.5 mM MgCl₂, 10 mM HEPES, and 15 mM dextrose, adjusted to a pH of 7.2 with NaOH. At the conclusion of the recording the entire cell was harvested via the recording pipette by negative pressure and stored in first-strand buffer at −80° C. until needed. Data acquisition was performed using PClamp V8.1 software and the Axopatch 200A (Axon Instruments, Union City, Calif.). Data was filtered at 2 kHz (−3 dB) and sampled at 2 kHz. No leak correction or series resistance compensation was performed. Recordings were performed at room temperature.

[0196] Calcium Current Recordings

[0197] Acutely dissociated DRG neurons were placed into the recording chamber containing bathing solution (see above). Patch electrodes were fire polished to a resistance of 1-2 MΩ. The internal solution for perforated patch recordings consisted of 135 mM CsCl, 10 mM HEPES, 1 mM EGTA, 1 mM EDTA, 4 mM MgCl₂ and 1.2 mg/ml amphotericin (Sigma), adjusted to a pH of 7.2 with TEA-OH. Micropipettes were pre-filled with amphotericin-free solution and backfilled with internal solution containing amphotericin. Seals were formed in bathing solution. The series resistance decreased over a 20 min period and was considered acceptable when <12 MΩ. The bath solution was then replaced with 135 mM TEA-Cl, 2 mM CaCl₂, 10 mM HEPES, 100 nM TTX (Sigma), adjusted to a pH of 7.2 with TEA-OH. Whole cell calcium currents were recorded under constant bath perfusion. A current-voltage protocol from a holding potential of −80 mV with 50 ms test pulses was then delivered. ω-Ctx GVIA (3 μM; Calbiochem, San Diego, Calif.) was applied directly onto the cell via a pipette using positive pressure. Test pulses were applied every 20 seconds to monitor toxin block which was considered saturated when current amplitudes were constant over a period of 1 minute. ω-Ctx GVIA was completely removed from the bath and a second current-voltage relationship obtained. Finally, the bath was exchanged with Na-containing solution, the cell voltage clamped to −60 mV, and challenged with 2 μM capsaicin. The entire cell was then harvested and stored in first-strand buffer at −80° C. After each application of ω-Ctx GVIA, the recording chamber was soaked in 2% SDS and 10 mM DTT for 15 min to remove any residual ω-Ctx GVIA. Data acquisition was performed using pClamp V8.1 software and the Axopatch 200A (Axon Instruments). For recordings calcium currents, data was filtered at 2 kHz (−3 dB) and sampled at 20 kHz. The series resistance was compensated by 70-90% with a 10 μs lag. Leak correction was performed with a P/−4 protocol. All recordings were obtained at room temperature.

[0198] The Low Threshold Component in Toxin-Subtracted Currents from Capsaicin-Nonresponsive Cells

[0199] A low threshold calcium current was prominent in capsaicin-non-responsive cells (FIG. 15a). This current deactivated with slow kinetics, typical of T-type currents but it was also labile. Current amplitudes declined to 52±2% of initial values over a 5 minute period (measured at −40 mV, n=3) compared to a decline to 89±1% for the high threshold current (at −10 mV, n=3). Relatively rapid run-down of the low threshold current likely explains the presence of a low threshold current showing up in the ω-Ctx GVIA-sensitive current voltage relationship. It is also possible that other low threshold calcium currents contribute to this component of the current voltage-relationship. For example, Ca_(V)1.3 L-type currents that activate at relatively negative voltages (Lipscombe, 2002). There are reports that the Ca_(V)1.3 L-type current is inhibited by high concentrations of ω-Ctx GVIA (Williams et al., 1992b), however, our studies of neuronal Ca_(V)1.3 L-type channels suggest that they are not ω-Ctx GVIA-sensitive (Xu and Lipscombe, 2001).

[0200] Single Cell RT-PCR

[0201] After harvesting the entire neuron into the recording pipette via negative pressure, the tip of the pipette and its contents (˜2 μl) were broken into a thin-walled PCR tube containing water and first-strand buffer. cDNA was synthesized from single cells using Superscript II (Invitrogen) and used as template for subsequent PCR reactions with the Advantage2 PCR system (BD Biosciences Clontech, Palo Alto, Calif.). One round of PCR was performed using a Robocyler (Stratagene, La Jolla, Calif.) on single cell cDNA. For all sets of primers the PCR reaction conditions were 1 cycle of 94° C. for 3 min; 35 cycles of 94° C. for 1 min, 59° C. for 1.5 min, 72° C. for 1.5 min, and a final 7 min extension at 72° C. Products were then run out on 2% standard agarose or 4% Metaphor agarose gels. Band intensities were directly quantified from gels using a digital analysis system (Alpha Innotech). PCR products from single cells were subcloned and sequenced to confirm their identity. Negative controls lacking cDNA were performed and processed in parallel with single cell RT-PCR reactions (1 negative control for every 6 cells). The negative controls included recording pipettes used for whole cell recording. To prevent contamination all PCR reactions were performed in a separate room not previously exposed to Ca_(V)2.2 clones. Internal solutions were RNAse free. RT-PCR primers were located in different exons to avoid amplification of genomic DNA. RT-PCR reagents and enzymes were always divided into aliquots to screen single cells in groups of ˜50 neurons with identical stocks of RT-PCR reagents and enzymes. This reduced variability. The PCR primer sequences and their predicted PCR product sizes were as follows: r18a-up, 5′cgcaggttctggagccttagct; (SEQ ID NO: 5) r18a-dw, 5′ggccattgctgtggacaacctt. (SEQ ID NO: 6) (227 and 290 bp for .18a and +18a) r24a-up, 5′cattctggacttcattgttgtcagtgga; (SEQ ID NO: 7) r24a-dw, 5′tcgcaggactctcagagacttgatggta. (SEQ ID NO: 8) (114 and 126 bp for .24a and +24a) r31a-up, 5′cagagatgcctggaacgtctttgac; (SEQ ID NO: 9) r31a-dw, 5′ataacaagatgcggatggtgtagcc. (SEQ ID NO: 10) (169 and 175 bp for .31a and +31a) r37a-up, 5′agctgcgtgttgccggattcattataagga; (SEQ ID NO: 11) r37a-dw, 5′gcgcttgtaggccaacctacgagggcagtt. (SEQ ID NO: 12) (108 bp) r37b-up, 5′agctgcgtgtgggcgcatcagttacaatga; (SEQ ID NO: 13) r37b-dw, 5′gcgcttgtatgcaactcgagccgggcattt. (SEQ ID NO: 14) (108 bp) rVR1-up, 5′tcaattcccacacacctcccagttcc; (SEQ ID NO: 15) rVR1-dw, 5′tttgggtggtctgcttagggaaccag. (SEQ ID NO: 16) (125 bp) rNaV1.8-up, 5′gcgctggttgtaagggtcagattg; (SEQ ID NO: 17) rNaV1.8-dw, 5′agccaggcaacaattgcagaaatc. (SEQ ID NO: 18) (245 bp) rGAPDH-up, 5′cagcaccagcatcaccccattt; (SEQ ID NO: 19) rGAPDH-dw, 5′caagatggtgaaggtcggtgtgaa. (SEQ ID NO: 20) (274 bp)

[0202] Competitive template for e37a, 5′agctgcgtgttgccggattcattataaggat (SEQ ID NO: 21) aagcgtgctggactctctcgacgcaaatcgagg cccaattggcaaatacagttgcagaacaggagg agccacacaactgccctcgtaggttggcctaca agcgc; (135 bp) for e37b, 5′agctgcgtgtgggcgcatcagttgcaatgat (SEQ ID NO: 22) aagcgtgctggactctctcgacgcaaatcgagg cccaattggcaaat acagttgcagaacaggag gagccacacaaaagcccggctcgagttgcatac aagcgc. (135 bp)

[0203] Oocyte Expression and Physiology

[0204] Complementary RNAs (cRNAs) were synthesized in vitro using the Ambion mMessage machine RNA transcription kit using T-7 primer (Ambion, Austin, Tex.). 1 μl of each Ca_(V)2.2 cRNA preparation was run out on a denaturing formaldehyde gel along with cRNA standards. Band intensities were directly quantified using a digital analysis system (Quantity-One, Bio-Rad, Hercules, Calif.) to ensure equal amounts of Ca_(V)2.2e[37a] and Ca_(V)2.2e[37b] cRNAs. Full-length cRNAs were mixed in equimolar ratios, 5 ng of Ca_(V)2.2, 1.6 ng of Ca_(V)β3, and 2.6 ng of Ca_(V)α₂δ in a total volume of 46 nl, and injected into individual defolliculated oocytes. Four separate rounds of oocyte injections were performed. N-type calcium currents were recorded 4-6 days after injection by standard two microelectrode voltage clamp technique (Warner amplifier; OC-725b) and the data collected using pClamp6 software (Axon Instruments, Union City, Calif.). Microelectrodes were filled with 3M KCl and the resistances of the current and voltage electrodes were 0.3-1.5 MΩ. Data were filtered at 0.5 kHz and sampled at 10 kHz. Currents were recorded in a reduced chloride bathing solution containing: 5 mM Ba(OH)₂, 5 mM HEPES, 85 mM TEA-OH, and 2 mM KOH, pH adjusted to 7.4 with methanesulfonic acid. N-type currents ranged between 0.1 μA and 0.6 μA. Leak and capacitive currents were subtracted online using a P/−4 protocol (Pclamp, V6.0; Axon Instruments).

[0205] Results

[0206] Multiple Ca_(V)2.2 Splice Isoforms are Expressed in Dorsal Root Ganglia

[0207] The Ca_(V)2.2 gene is subject to alternative splicing and dorsal root ganglia express multiple splice isoforms (FIG. 10a, b). Cassette exons e18a, e24a, and e31a are either present or not in the final mRNAs. Their expression patterns have been reasonably well characterized at the whole tissue level. The majority of Ca_(V)2.2 mRNA in dorsal root ganglia contains e31a, consistent with preferential expression of this exon in peripheral ganglia. Splice isoforms of Ca_(V)2.2 both containing and lacking e18a and e24a are also present (FIG. 10b). The splicing patterns of e18a, e24a, and e31a of Ca_(V)2.2 at the whole tissue level is consistent with previous analyses by RT-PCR and ribonuclease protection in rat DRG (Lin et al., 1997; Lin et al., 1999; Pan and Lipscombe, 2000) and for equivalent exons 24a and 31a in chick DRG (Lu and Dunlap, 1999). These analyses of whole tissue, however, do not address whether the pattern of alternative splicing varies among individual neurons. Sensitivity to capsaicin is commonly used as a functional marker to identify a subtype of nociceptive neuron (Caterina and Julius, 2001; Caterina et al., 1997; Tominaga et al., 1998). We therefore used whole-cell recording to separate neurons into two groups based on capsaicin-responsiveness, and then analyzed each site of alternative splicing in the same neurons by single cell RT-PCR.

[0208] Screening Neurons of the Dorsal Root Ganglia by Capsaicin-Responsiveness

[0209] Neurons of the dorsal root ganglia were voltage-clamped at −80 mV, and brief depolarizations applied to establish the presence of robust voltage-gated potassium and sodium currents characteristic of viable neurons. Subsequently, the membrane potential was voltage-clamped to −60 mV and neurons exposed to 2 μM capsaicin (FIG. 1a, b; n=128 capsaicin-responsive neurons and n=141 non-responsive neurons). Capsaicin exerts its effects via activation of the vanilloid receptor (VR1). Consistent with this, we detected VR1 mRNA in 89% of capsaicin-responsive cells (25 of 28) whereas only 13% of non-responsive cells contained VR1 mRNA (2 of 15) (FIG. 11c, d).

[0210] Individual DRG Neurons Express Multiple Ca_(V)2.2 Splice Isoforms

[0211] We analyzed e18a, e24a, and e31a at the single cell level and demonstrated that the pattern of alternative splicing varied among individual neurons. Some cells expressed both isoforms of a particular splice site, while other cells expressed one form (FIG. 12). For example, all neurons expressed Ca_(V)2.2 mRNAs that lacked e18a (FIG. 12a, n=38 cells). While only a sub-set also expressed Ca_(V)2.2 mRNAs containing e18a. We observed a pattern of alternative splicing similar to this for the e24a site (FIG. 12b, n=38). However, there was no correlation between the inclusion or exclusion of a particular exon and capsaicin-responsiveness (FIG. 12a, b). We detected e31a in all neurons analyzed regardless of capsaicin responsiveness. Ca_(V)2.2 mRNAs lacking e31a were not detected (FIG. 12c; n=18). This reflects the splicing pattern of e31a observed at the whole tissue level and is consistent with the proposal that the vast majority of Ca_(V)2.2 mRNAs expressed in peripheral ganglia, including DRG, contain e31a (Lin et al., 1997; Lin et al., 1999; Lu and Dunlap, 1999).

[0212] Exon 37a is Only Expressed in Dorsal Root Ganglia

[0213] We examined a fourth site of alternative splicing, located in the C-terminus, that had been identified based on analysis of human genomic sequence (Lipscombe, 2003; Lipscombe et al., 2002; Soong et al., 2002). The presence of tandem exons, e37a and e37b in genomic sequence, identical in length (97 nucleotides) and differing by only 14 amino acids is consistent with a mechanism of mutually exclusive splicing (FIG. 13a). However, despite evidence for the presence of these two homologous exons of Ca_(V)2.2 in the public genome sequence of human, rat and mouse, all Ca_(V)2.2 mRNAs analyzed to date contain e37b. No mammalian Ca_(V)2.2 mRNA containing e37a has been reported. We designed two sets of exon-specific PCR primers, because e37a and e37b are indistinguishable on the basis of size. We analyzed their expression patterns in rat, initially at the whole tissue level. As expected, Ca_(V)2.2e[37b] mRNAs were expressed throughout the central nervous system and in both sympathetic and dorsal root ganglia. In sharp contrast, we found expression of e37a highly restricted and only present at significant levels in dorsal root ganglia (FIG. 13b). Our results explain why Ca_(V)2.2e[37a] cDNAs were not isolated in earlier cloning efforts because tissue from dorsal root ganglia was not used (Cahill et al., 2000; Coppola et al., 1994; Dubel et al., 1992; Fujita et al., 1993; Lin et al., 1997; Williams et al., 1992a). Our use of exon-specific primers, however, does not provide information on the relative levels of Ca_(V)2.2e[37a] and Ca_(V)2.2e[37b] mRNAs. The high efficiency of PCR could result in significant product even if starting levels of Ca_(V)2.2e[37a] mRNAs are low in number. We therefore employed a competitive RT-PCR protocol and established that Ca_(V)2.2e[37a] mRNAs are present in whole DRG of P5 and adult animals at levels only 10-fold lower compared to Ca_(V)2.2e[37b] (FIGS. 13c and 13 d). The Ca_(V)2.2e[37a] splice isoform therefore represents a significant fraction of the total Ca_(V)2.2 mRNA pool in dorsal root ganglia. We next tested the possibility that e37a expression is regulated at the single cell level and perhaps linked to functionally distinct sub-types of sensory neurons.

[0214] Preferential Expression of Exon e37a in a Subset of Capsaicin-Responsive Neurons

[0215] We separated neurons of the dorsal root ganglia on the basis of capsaicin-responsiveness and analyzed each cell by RT-PCR using e37a and e37b-specific primers. All neurons tested with e37b-specific primers contained e37b (n=48; FIG. 14a, 14 d). This is consistent with the ubiquitous expression pattern of this splice form of Ca_(V)2.2 (FIG. 13b) and also serves as an important control establishing that Ca_(V)2.2 mRNA is expressed in every neuron. By contrast, only a sub-set of neurons expressed e37a. Most significantly, the e37a splice isoform was expressed preferentially in capsaicinresponsive neurons (55% of capsaicin-responsive compared to 17% of non-responsive neurons; FIG. 14b, 14 d). Capsaicin-sensitivity is often used as a marker for nociceptors but it only identifies a sub-set of these cells. We therefore assayed for the presence of the TTX-resistant sodium channel, Na_(V)1.8, that is restricted to nociceptors (Akopian et al., 1996; Dib-Hajj et al., 1998). Using Na_(V)1.8-specific primers we found that 80% of capsaicin-responsive neurons analyzed express Na_(V)1.8 mRNA (19 of 24; FIG. 14c, 14 e). Most significantly, all neurons that expressed e37a also expressed Na_(V)1.8 (14 of 14; FIG. 14c, 14 e) establishing a strong link between a second molecular marker of nociceptors and the presence of Ca_(V)2.2 mRNA containing e37a. Importantly, we next assessed the functional consequences of cell-specific expression of Ca_(V)2.2e[37a] on the N-type current.

[0216] Calcium Currents in Capsaicin-Responsive and Non-Responsive Neurons

[0217] We used the perforated, whole-cell patch recording method to record calcium currents from neurons of the dorsal root ganglia (Horn and Marty, 1988). 2 mM calcium was the charge carrier. Capsaicin-responsive neurons were significantly smaller in size on average (18±3 pF), compared to non-responsive neurons (27 pF±3) (p<0.001) as reported by others (Cardenas et al., 1995). Initially, the most obvious difference among cells when we separated them on the basis of capsaicin-sensitivity was the presence of a significantly larger low threshold Ca current in non-responsive neurons. This low threshold component is prominent in exemplar current traces and in the average current voltage-relationships from non-responsive neurons (FIG. 15a). In this regard, our findings are consistent with the reports of others (Blair and Bean, 2002; Carbone and Lux, 1984; Cardenas et al., 1995; Schroeder et al., 1990; Scroggs and Fox, 1992a). The high threshold component of the whole cell calcium channel current originates from the activity of additional classes of calcium channel including N-type (Regan et al., 1991; Scroggs and Fox, 1992a). On first inspection, the multi-component, high voltage-activated current appeared similar between capsaicin-responsive and non-responsive neurons (FIG. 15a, activation mid-points for the high voltage-activated currents were close to −15 mV). For this study, we were specifically interested in the N-type current and isolated it from other voltage-activated calcium currents by toxin-subtraction using ω-conotoxin GVIA (ω-Ctx GVIA) (Regan et al., 1991; Scroggs and Fox, 1992b).

[0218] N-type Currents in Capsaicin-Responsive and Non-Responsive Neurons

[0219] Consistent with other reports, the ω-Ctx GVIA-sensitive, N-type current was the major component of the total Ca current in capsaicin-responsive and non-responsive neurons (˜70%; FIG. 15b) (Regan et al., 1991; Scroggs and Fox, 1992a). The N-type current was well isolated in capsaicin-responsive neurons although in non-responsive neurons a small low-threshold current was still present in toxin-subtracted currents (FIG. 15b). The low threshold current runs down relatively rapidly even in the absence of toxin, and this is the most likely explanation for its presence in toxin-subtracted current-voltage relationships of non-responsive neurons (see Methods section for further details). Most importantly, after isolating the N-type current we revealed significant differences in peak N-type channel current densities between capsaicin-responsive 111±12 pA/pF (n=20) and non-responsive neurons 72±8 pA/pF (n=9) (FIG. 15b; p<0.05). Although significantly larger, the biophysical properties of N-type currents in capsaicin-responsive neurons were not distinguishable from non-responsive neurons (V_(1/2) and k values for non-responsive neurons were: −16±2 mV and 5.4±0.6, n=9, compared to −15±1 mV and 5.2±0.3 for responsive neurons, n=20; FIG. 15b). Our data suggests that capsaicin-responsiveness is linked to a significantly greater number of functional N-type channels.

[0220] Exon 37a is Linked to Larger N-type Current Density in Capsaicin-Responsive Neurons

[0221] Having demonstrated preferential expression of a unique splice isoform of Ca_(V)2.2 in a sub-set of capsaicin-responsive neurons (FIG. 14b-d), we tested the hypothesis that the presence of Ca_(V)2.2e[37a] was linked to larger N-type current densities. We selected only capsaicin-responsive neurons, analyzed the N-type current, harvested these same cells, and performed RT-PCR to assay for the presence of each of Ca_(V)2.2e[37a], Ca_(V)2.2e[37b], and GAPDH. We performed this complete series of manipulations on 16 individual capsaicin-responsive neurons. These were subsequently separated into two pools, those that expressed Ca_(V)2.2e[37a] mRNA and those that did not. FIG. 16 summarizes our results and reveals a significant difference in N-type current densities between cells that contain and lack Ca_(V)2.2e[37a]. Capsaicin-responsive neurons that contained and lacked exon 37a were not distinguishable based on cell size, consistent with them representing a relatively homogenous population of nociceptors (20±3 pF, n=8, and 18±1 pF, n=8, for e37a-containing and lacking, respectively). The presence of the Ca_(V)2.2e[37a] splice isoform was, however, associated with 1.6-fold larger N-type currents (peak current densities were 122±11 pA/pF, n=8, in cells containing e37a compared to 76±3 pA/pF, n=8, in cells lacking e37a; p<0.05; FIG. 16). We also compared the basic biophysical properties of the N-type currents. The voltage-dependence of N-type channel activation, as well as the kinetics of activation and inactivation is not significantly different in cells containing and lacking exon 37a, despite their very different current densities (FIG. 16a-c).

[0222] Exon 37a Induces Larger N-type Currents in a Non-Neuronal Expression System

[0223] To establish a direct link between expression of the Ca_(V)2.2e[37a] splice isoform and larger N-type channel current amplitudes, and to eliminate the potential contribution of other factors, we compared Ca_(V)2.2e[37a] and Ca_(V)2.2e[37b] clones expressed in Xenopus oocytes under identical conditions. The resultant N-type channel currents were compared in detail and our analysis summarized in FIG. 17. N-type channel currents in oocytes injected with Ca_(V)2.2e[37a] cRNA were consistently and significantly larger than those in oocytes injected with the same amount of Ca_(V)2.2e[37b] cRNA (1.6-fold, p<0.05; FIG. 17). Currents were recorded under identical conditions and the same complement of auxiliary subunits co-expressed. These differences between isoforms were observed over a three-day period (see legend to FIG. 17). We also compared the biophysical properties of the two splice isoforms. The voltage-dependence and kinetics of N-type channel activation were different between Ca_(V)2.2e[37a] and Ca_(V)2.2e[37b] channels. Ca_(V)2.2e[37a] channels activated at voltages 8 mV more hyperpolarized and with slightly faster kinetics at the same voltages, compared to Ca_(V)2.2e[37b] (FIG. 17b). To estimate the effect of left shifting the Ca_(V)2.2 channel activation on current amplitude, we plotted the predicted current-voltage relationship for Ca_(V)2.2e[37b] using the activation curve for Ca_(V)2.2e[37a] (FIG. 17a, dashed line). An 8 mV shift in activation results in a small increase in peak current because of the greater driving force on ions at hyperpolarized voltages, but this is insufficient to account for the 1.6-fold difference in peak current amplitudes between Ca_(V)2.2e[37a] and Ca_(V)2.2e[37b]. We also demonstrated that the voltage-dependence and kinetics of channel inactivation were indistinguishable between splice isoforms (FIG. 17c and see legend). These latter results exclude the possibility that differences in sensitivity to steady-state inactivation between splice isoforms might underlie their different current amplitudes.

[0224] Discussion

[0225] N-type calcium channels are critical for the transduction of pain in nociceptive neurons of dorsal root ganglia. Here we identify a novel splice form of the N-type Ca_(V)2.2 subunit restricted to dorsal root ganglia, and within this tissue, preferentially expressed in a subset of nociceptive neurons. mRNA levels of this Ca_(V)2.2 splice isoform are substantial and e37a-containing Ca_(V)2.2 mRNA strongly correlates with significantly larger N-type calcium current densities. Cell-specific alternative splicing at the e37a/e37b locus of Ca_(V)2.2 provides a mechanism for increasing N-type current density down-stream of gene transcription.

[0226] Functional Implications

[0227] The crucial role for the N-type channel in nociception is supported by several lines of evidence including the localization of N-type channels at primary synapses of nociceptive neurons in the dorsal horn laminae I/II (Kerr et al., 1988), dominance in controlling neurotransmitter release from presynaptic terminals of nociceptive neurons (Holz et al., 1988; Maggi et al., 1990), impaired nociception in mice lacking Ca_(V)2.2 (Hatakeyama et al., 2001; Kim et al., 2001; Saegusa et al., 2001), and powerful analgesic properties of spinally-administrated N-type channel blockers in a variety of animal pain models (Bowersox et al., 1996; Bowersox and Luther, 1998; Bowersox et al., 1995; Matthews and Dickenson, 2001; Vanegas and Schaible, 2000). The N-type channel is a target for modulation by many neuromodulators and second messenger signaling pathways. Most neuromodulators, including morphine, couple to the N-type channel to inhibit its activity and down-regulate transmitter release (Ikeda and Dunlap, 1999). Here, we describe a mechanism for increasing the activity of the N-type current in a sub-set of nociceptive neurons that has the potential to increase the coupling efficiency between depolarization and transmitter release, thereby modifying the transmission of noxious stimuli. A characteristic feature of nociceptive neurons is their unusually wide action potentials that have a signature shoulder phase (Blair and Bean, 2002; Djouhri et al., 1998; Dunlap and Fischbach, 1978; Harper and Lawson, 1985; Heyman and Rang, 1985; Ritter and Mendell, 1992). High voltage-activated calcium channels, predominantly N-type, together with TTX-resistant sodium channels are the main contributors to the plateau phase (Baccei and Kocsis, 2000; Blair and Bean, 2002; Renganathan et al., 2001; Scroggs and Fox, 1992b). Cell-specific alternative splicing of e37a in nociceptive neurons also represents a potential mechanism for shaping action potential duration by increasing N-type current density. Although other ion channels clearly remain important, it would be interesting to determine if a correlation exists between levels of e37a and action potential half-widths in single cells. Inclusion of e37a during the processing of Ca_(V)2.2 RNA is cell-specific, raising the possibility that this splicing event might be regulated by specific stimuli or level of neuronal activity. For example, alternative splicing of the STREX exon in the calcium-activated potassium channel, slo, is regulated by stress hormones and membrane depolarization (Xie and Black, 2001; Xie and McCobb, 1998). mRNA and protein levels of the calcium channel Ca_(V)α2δ subunit protein have been reported to be elevated in dorsal root ganglia in a rat injury model (Luo et al., 2001). The Ca_(V)α2δ subunit modifies calcium channel properties and increases channel surface expression (Felix, 1999; Witcher et al., 1993). Although total levels of Ca_(V)2.2 mRNA were reportedly unchanged in the same study (Luo et al., 2001) the splicing pattern at the e37a/e37b locus was not analyzed. Our data suggests that a shift in the splicing pattern from e37bcontaining to e37a-containing Ca_(V)2.2 mRNA could provide a powerful and relatively rapid mechanism, independent of gene transcription, for increasing N-type current density in the pain pathway.

[0228] Mechanism of Action of Exon 37a

[0229] Our experiments in Xenopus oocytes with cloned Ca_(V)2.2 channels demonstrate a direct link between the presence of exon 37a and significantly larger N-type currents. In this respect our studies of cloned channels parallel nicely those of native N-type currents in capsaicin-responsive neurons. Although other factors need to be ruled out, such as differences in single channel conductance, our results are most consistent with the hypothesis that Ca_(V)2.2e[37a] splice isoforms produce a greater number of functional N-type channels compared to Ca_(V)2.2e[37b]. Our analysis of Ca_(V)2.2e[37a] and Ca_(V)2.2e[37b] currents recorded from oocytes did, however, also reveal differences in the voltage-dependence and kinetics of N-type channel activation. By contrast, the biophysical properties of native N-type currents isolated by conotoxin-subtraction were not significantly different in capsaicin-responsive cells separated based on the presence and absence of Ca_(V)2.2e[37a] (FIG. 16a-c). It is possible that the biophysical properties that differ between splice isoforms in the oocyte expression system are present in native currents, but masked in our analysis by a combination of the toxin-subtraction method and the presence of other splice isoforms with different properties (FIG. 10) (Lipscombe et al., 2002). While insufficient alone to account for the different current amplitudes, if present in neurons, such biophysical differences between splice isoforms would combine with the increased effectiveness of Ca_(V)2.2e[37a] mRNA, to induce larger N-type currents and increase calcium entry through the N-type pathway. Our oocyte experiments demonstrate that the mechanisms underling the different N-type current amplitudes induced by splice isoforms are not unique to neurons, and further, that the information necessary to mediate these differences are contained in the 14 amino acids that are different between Ca_(V)2.2e[37a] and Ca_(V)2.2e[37b] (FIG. 13a). The 37a/37b splice site is located in the C-terminus of Ca_(V)2.2, a region implicated in the trafficking and targeting of calcium channels (Gao et al., 2000; Maximov and Bezprozvanny, 2002; Maximov et al., 1999). It is possible that the Ca_(V)2.2e[37a] isoform is more efficiently targeted to the plasma membrane, although other mechanisms including differences in protein stability cannot be ruled out. The C-terminus of Ca_(V)2.2 constitutes ˜25% of the channel protein and is encoded by exons 36-46 (FIG. 10a). It contains several protein binding sites including those that bind G-proteins, Mintl, CASK, and RIM binding proteins (Hibino et al., 2002; Maximov et al., 1999; Simen et al., 2001). However, these sites fall distal to the e37a/e37b locus. Further, all binding studies using recombinant Ca_(V)2.2 protein to date have been performed with the e37b-containing splice form. A comparison of amino acid sequences suggests that e37a modifies a putative EF-hand motif present in e37b. However, so far we have not observed calcium-dependent differences between splice forms transiently expressed in a mammalian cell line even with low internal calcium buffering. Exons homologous to e37a and e37b are present in the closely related Ca_(V)2.1 gene of the P/Qtype channel and are also predicted to modify a putative EF-hand motif (Soong et al., 2002). The functional significance of splicing at the e37a/e37b locus in Ca_(V)2.1 is not known.

[0230] Potential Therapeutic Implications

[0231] N-type channel antagonists that target sequences specific to e37a of Ca_(V)2.2, could offer significant benefits over current N-type blockers such as SNX-111 that have been used with limited success as analgesics because of undesirable side effects. These include inhibition of sympathetic tone, disrupted motor coordination, and dizziness and blurred vision (Bowersox et al., 1996; Brose et al., 1997; Chaplan et al., 1994; Vanegas and Schaible, 2000). Selective inhibition of the e37a splice form of Ca_(V)2.2 represents a potential strategy for targeting N-type currents in a subset of nociceptive neurons while leaving basal transmission mediated by the N-type channel unaffected. It will now be important to determine the sub-cellular distribution of these splice forms of Ca_(V)2.2 in nociceptive neurons using exon-specific antibodies. Other splice forms of the Ca_(V)2.2 subunit arising from alternative splicing at a different locus in the C-terminus have been reported that are differentially targeted in the cell (Maximov and Bezprozvanny, 2002). Cell-specific alternative splicing of other ion channels exists (Black, 1998; Jones et al., 1999; Navaratnam et al., 1997; Rosenblatt et al., 1997) and offers a powerful means to fine-tune the properties of channel activity down-stream of transcription. We demonstrate cell-specific alternative splicing of the N-type Ca channel in a subset of nociceptive neurons and suggest that this offers a mechanism for increasing the efficiency of coupling between membrane depolarization and calcium entry in the pain pathway.

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[0302] Each of the foregoing patents, patent applications and references is hereby incorporated by reference.

[0303] While the invention has been described with respect to certain embodiments, it should be appreciated that many modifications and changes may be made by those of ordinary skill in the art without departing from the spirit of the invention. It is intended that such modification, changes and equivalents fall within the scope of the following claims.

1 47 1 24 DNA Artificial PCR primer 1 gctgcgtgtt gccggattca ttat 24 2 24 DNA Artificial PCR primer 2 ttcattcgaa ccaggcgctt gtag 24 3 24 DNA Artificial PCR primer 3 ctgaatacga cccagctgcg tgtg 24 4 24 DNA Artificial PCR primer 4 ccaggcgctt gtatgcaact cgag 24 5 22 DNA Artificial PCR primer 5 cgcaggttct ggagccttag ct 22 6 22 DNA Artificial PCR primer 6 ggccattgct gtggacaacc tt 22 7 28 DNA Artificial PCR primer 7 cattctggac ttcattgttg tcagtgga 28 8 28 DNA Artificial PCR primer 8 tcgcaggact ctcagagact tgatggta 28 9 25 DNA Artificial PCR primer 9 cagagatgcc tggaacgtct ttgac 25 10 25 DNA Artificial PCR primer 10 ataacaagat gcggatggtg tagcc 25 11 30 DNA Artificial PCR primer 11 agctgcgtgt tgccggattc attataagga 30 12 30 DNA Artificial PCR primer 12 gcgcttgtag gccaacctac gagggcagtt 30 13 30 DNA Artificial PCR primer 13 agctgcgtgt gggcgcatca gttacaatga 30 14 30 DNA Artificial PCR primer 14 gcgcttgtat gcaactcgag ccgggcattt 30 15 26 DNA Artificial PCR primer 15 tcaattccca cacacctccc agttcc 26 16 26 DNA Artificial PCR primer 16 tttgggtggt ctgcttaggg aaccag 26 17 24 DNA Artificial PCR primer 17 gcgctggttg taagggtcag attg 24 18 24 DNA Artificial PCR primer 18 agccaggcaa caattgcaga aatc 24 19 22 DNA Artificial PCR primer 19 cagcaccagc atcaccccat tt 22 20 24 DNA Artificial PCR primer 20 caagatggtg aaggtcggtg tgaa 24 21 135 DNA Artificial Competitive template for exon 37a 21 agctgcgtgt tgccggattc attataagga taagcgtgct ggactctctc gacgcaaatc 60 gaggcccaat tggcaaatac agttgcagaa caggaggagc cacacaactg ccctcgtagg 120 ttggcctaca agcgc 135 22 135 DNA Artificial Competitive template for exon 37b 22 agctgcgtgt gggcgcatca gttgcaatga taagcgtgct ggactctctc gacgcaaatc 60 gaggcccaat tggcaaatac agttgcagaa caggaggagc cacacaaaag cccggctcga 120 gttgcataca agcgc 135 23 9562 DNA Rattus norvegicus exon (1)..(128) Exon 36, continues 5′ to nt 1 23 atg ctg aac ctc ttt gtt gct gtg atc atg gac aat ttc gaa tac ctc 48 Met Leu Asn Leu Phe Val Ala Val Ile Met Asp Asn Phe Glu Tyr Leu 1 5 10 15 acg cgg gat tct tcc atc cta ggg ccg cac cac ctc gat gaa ttc att 96 Thr Arg Asp Ser Ser Ile Leu Gly Pro His His Leu Asp Glu Phe Ile 20 25 30 cgc gtc tgg gct gaa tac gac cca gct gcg tg gtgagtgagc tccagtgctc 148 Arg Val Trp Ala Glu Tyr Asp Pro Ala Ala Cys 35 40 tctgctcctc agggttggct gccattgcct gtggttctcc agacagggcc agggtgatct 208 tagacagttc catgtgcatg tccctaggtg ttgggctgag gtctagtgac ttacccagtt 268 ctgtgtgtgg tagcactggt ccccttgcag tagcatgttt cttttgatcc cgtgccttgg 328 tgcagctgtg gggcagagac actaagtatg gtcctcaaag agagtgccta tgcctggggg 388 tcaaggaaca tttccagggc tctttgcaca gaagtgtcct gccttctccc aaggcttgtc 448 ttgtgatgga acatggaggc ccagtggcgg agggtagaga gagagtgtag ggacacatct 508 gtgtaatact cagagggtgt tgagagcaaa tgatgtgtgt gtatgtgttt gggaggggtg 568 tggttgctgc tgtggctgtt gttgtttaaa gaattgggga ctgaaccctg ggacatgtaa 628 gtcaaaatac tttagcaact gagctgtatc ccccacttgc cataatgtga gtcttaaatt 688 ttttcttgat ggatttagtt tttcttctgc catttctttt ggggccagga gccagtgtgt 748 atgtctgttg ccagccttgt tttatgtggt gggcactggg tggaacttta ttcaaaccag 808 gggaattggg gaaatagaaa actgttaccg ggctgcataa gtgaagggtg atttgtttct 868 agatagcaag gaccttctgg attgctttgg gtgaaagtga aagttgtttg aagccatgtt 928 ccagagagag cattgcacag tgatgtcatg gtccatagag aacactgcac agtgatgtca 988 tggtccaaag ggagcactac acagtgatgt cacaatccgg agagagcact gcacagtgat 1048 gtcacagtnn nnnnnnnnac acagtgatat cacagtccat agagagcact gcacagtgat 1108 gtcacagtcc atagagagca ctgcacagtg atgtcacggt ccaaagggag cactacacag 1168 tgatgtcaca gtccatagag agcactgcac agtgatgtca tggtccaaag ggagcactac 1228 acagtgatgt cacggtccat agagagcact gcacagtgat gtcacggtcc atagggagca 1288 ctgcacagtg atgtcacggt ccatagggag cactgcacag tgatgtcacg gtccataggg 1348 agcattacac agtgatatca cagtccatag agagcactgc acagtgatgt catggtccat 1408 agggagcact gcacagtgat gtcatagtcc atagagaaca ctacacagtg atgtcacggt 1468 ccatagggag cactgcacag tgatgtcaca gtccatagag agcactgcac agtgatgtca 1528 cagtcaatca ataatactgc acgatgattg tcacaccaat cccctttgcc agagaccaca 1588 ttcaggaagg caggggagca ggacatcggg gctctccatc cgtgtgcttg ttcgtccctc 1648 tacccacttg gtcaccgaat tgatgcactc attgcgtctg ctcctacgcc ccaccatctc 1708 ctctcaccta cctgctcact tgtgtattgt gttagttacc ttttgattct gtgattggat 1768 ctcacaaaag caacttcagg caaaggcttg ctttggctta tgatttaaga ggagatatag 1828 tctaacacgg aaggaaggca catggcagga gcaggagacc gtgggtcaca atcatgggag 1888 atgagtgctg gtgtccatct cagtttactt tttattcagc ccgggaccct gacctgggat 1948 gatgccaagt acatttattg cgtggctctt cccatctcaa tccaatgtag ccgttccctc 2008 acagagaggg cgctcagagg cctgccttct gggtgcctct tgaccccgtt ctgctgacac 2068 ccacacatgc gctcacccag gtattttcca tttaatggct cattcgccca ttcatttgtt 2128 cagccgctca agtggtattt gcagacggct cttccttgta agggggcgtg caggaggggc 2188 agaggctcag agcactgact gctgtggaag atacaagcct ctcctctcac ctgccacagc 2248 tgtgaatggg cagttgtcct tgaaggagtg agtggtggcg tcctgtgcct tagggatgga 2308 caagaaactg cagctgtgtg cagttcctca ggcccccttg tctgcctctc ctaggttgtg 2368 gtcagcgttt tgctgtggga tagttgggag aatgaagtca ggctcctgtg gttagactgg 2428 gcatgctaag ctttctggta gaccctgggg gctgaagtca ggacaggcat gcttaggtct 2488 ctgctggagg actagaggat gtgaccaggc tgatggctag agtcctctgt ctcaagctcc 2548 taagcttctg cgtccttgac ctgatgccca gcacaagatg ctcagtaaac tccgggaagg 2608 ggtagtcagg ctttcttctg ctgggttaga tccccattgc ttctgtcctt cagcctctcc 2668 tctgcgccta gagacagata gatagactgc aggtgtcttc agttcctcag ctgcccttgt 2728 ctgcccctca cagtgtgttc tgaggttgtg cctggagttg tagccaggga agtttcacag 2788 tattgcatca gggtgctggg acagaggtct tttccgttgg ggctgtttgg actgacgtcc 2848 tctctgagtc tatttcccat tgctgtgaga aacctcccat ttttacatag ttcataagca 2908 gcacttattg ttgttgtgca ttacgcttga ctactttgac tctgtagacg attctctgtc 2968 tatattcata tgttttcccc accatgccca agactcttac tgagctgctc aggctcaagg 3028 atattgcact agctctgtgg ttaggtatgt caccgaggta gggtgcagtg gggagactgg 3088 actttgtcat ataaagggca ggagagactc cagcggcaaa atgactcatt tgatcttcaa 3148 gattaccctg gctatgacct caacagccat tgctatttct ggaatatttt cccaaggtgc 3208 aaagaacaga tggtctgtgg gactcactca cactgaaggc cagctgtgaa gggcagcatg 3268 gtgcttgccc tcatgaactg catacccagt tcctgccatc gactgtaacg aagaaggggt 3328 aacgggcaca gtggtgctta gcctgaggac agacttggga gcgtgcacag tgagagtgta 3388 gtctgtcttc taacttgaga gctagagagc taggggccct ggatgtcacc agcaagttga 3448 agagatggcc ttgtggtagg ggtgacacca tggccaaacg gcatccagat caagccgctt 3508 aaagatcagg tgaacttcaa agtgctttga gactggtgct tgttccctgc agaccccttt 3568 aggaggtgga tggcttgaca gagcactcaa acaggtcaaa gctggcagag caccatgcta 3628 aagctgggtc ctgcatttga acaggcttac ggtctgtctt aatttcctat gtgaccatgt 3688 gattttctca tcatttgggt aaaactttga aacgacaaac tgtcagactt tctaacattt 3748 gtgtatgtgt ctgcacaagc acagatgtgt gtgagcatat gcatgtgtgt atatgtggat 3808 gagcctgtgt gtcctctgca tgtgcacaca aaggcacatg catatgtttg tgtatccatg 3868 ttagtttgtg tgtgtgtgtg tgtgtgtgat acacatctgt gtatggtaag tatacatgtg 3928 tgttgtgtgc atgtgtgagt cattccatgt atttgtgcat tcctgttagg tgtttatgta 3988 ccacctgtac gttgtgtgaa cgtgtacatg ctgtgggata ctagaaaggc atggagcttc 4048 tgggagctgg agctgctctt tccccggcct cccttttgtt gcttcaaaac actgtgttga 4108 agcatgggga ccgaaagtga aagccatgct taccggtcgt ccatctgctg aggaaacact 4168 tcctgagcat ctgctctgtc ctgggcctgg ggccccaaag gtgaaagtgt aaatagggct 4228 gtgagatagg acagttagat gttcacagct tggggccagg gcacctttga ggagggaagg 4288 atcacgtgca cctaagctgt gtgaaaggag gcaagatgaa cggagtgtca ggcaactctg 4348 aggcaggtac agagagaggg agaactggga agatcgttga ggcttgagtg aaaatgttaa 4408 agctgggaga gattgagaga ccttgaaact gaagttaaac aggtaatttt gcttttgttt 4468 tacttgggaa aatattccca aacagggtta acgtgtatca tgtccacgca tttccactag 4528 tgttaaagaa tggacttgat gagtagttgg ccccttggaa ttgtccctag gatccaacaa 4588 gattagcaag tatgtgaggc ccaagtagaa tatcctcttt tctggaagca aactgagcac 4648 gacttaaagc ttgatgagca gcataggaga aagaagggtc tgctgtgcca aagggtatca 4708 tccccgtgag gagggctttt ctagttaggc cagcaaactc ccagggaaca ccagtgtgtt 4768 cccagggaga tgggaacaat cgagaggcat ctaggtgtgt attcctcagt agggtttctg 4828 tgtctgagaa atggagggga cacatcacag gagtaagggc cagggtgaga gggagacaaa 4888 gagaaaggct ctggcattca ggaactgagg gcaggacaga cagcaagtcc agttgggact 4948 ggtcagtggt ggggctcatg gtgggcgtgg ggtgtttgtt cttctgcatt attctgagta 5008 gttcctgctt agcctcacat ccaggcatta tcttggggct gacactttct ggggagcact 5068 ggacttcagg tcccactagg gagtagcctg tgtagctgta cccctcacct ccacctcaca 5128 gctcatcttc cattgcagcc tgggtgggtg ggggacgggt tccatcctgc ctgttgccgt 5188 aacctgtgac atttcctttc cag t tgc cgg att cat tat aag gat atg tac 5239 Cys Arg Ile His Tyr Lys Asp Met Tyr 45 50 agt ttg ttg cgt tgt att gcg cca ccc gtt ggc tta ggg aag aac tgc 5287 Ser Leu Leu Arg Cys Ile Ala Pro Pro Val Gly Leu Gly Lys Asn Cys 55 60 65 cct cgt agg ttg gcc tac aag gtttgtaact tcagagcctc catctgacat 5338 Pro Arg Arg Leu Ala Tyr Lys 70 75 accccccgcc cgaatcgcac acactgcaca cactccctgc ctgacttggg aatgacaaca 5398 cctcaccttc tctttcctct gtcctgccct gccctgcgtt ccagcatcct ggatgctttg 5458 gttccctgtc ttatgtcccc tagctggagg caggcagcct tcatgacagt gtctgagatg 5518 gtttctggcc tggctcggcg gagtctgcca ggaccaattg gctgggcgtg ggggttaggg 5578 agggggttgg catgtggttg agacaggtcc cacctttacc aagcaaacag ccatcacacc 5638 cagcaatcct gcaggctctt atgattgggc tgatggtccg acagccagag gctgagagcc 5698 gagaggagaa tttgtacatg ggtgcaaata aacaaggagc agttgtccct gtgggtcagg 5758 agaggctctc aggtccctgg gggaggggag agtgggaaca agaaagggga gcccccctgc 5818 gtcgcttccg gattgatgtg ctcagctcag ggagaaaacc cctggcctgg aactgtgagt 5878 gaagggcagg gtctgggcag atctgccctc tggagaaagg ctggactctg ctgtgtctct 5938 gagaccccaa gcccacaggc aggtgctctg gggtagaggg aagccccagc ctcttgactt 5998 gggaagatgc tacaccagcc ccaagatgct gccctgagtg ccccagccca caggggcgca 6058 tccaacctgt tggtcccaac ctgtgctgtc agaggcacta gtggcaccag gccacagctt 6118 actcagctcc tcccttcccg cagtctcctt cccatccagc cctgacttca gcagcagccc 6178 tgccctgggc tggcctcggg cgtctctggg cttggagctg acttgccctg tcattcagtt 6238 cagtcactaa gaactttggg actccctttc tagctttcta atctgttgta gacttttctc 6298 cacattagcc tccggcctta tgtggaagca aatccaatct gcccattgag gtgggcgaca 6358 ctgctgctgt ggttctcagc ggtagtctcc tctccacagt ctggccagtg cttcccgtgc 6418 catgaaccag ctctttctga tttggccttg tctgcagttc taaaacagta aagtcagaaa 6478 tttataaccc aaagccgccc cgatgcagcc cttcctcacc cctccatgtt cattagctca 6538 gacatcaccc ctgcccgctg ccctgcattg ggctgcctat gaggaggtga ggctgggggt 6598 gggggcaagc aagggtcaag tcaagcagag ataccttcat tttacttgtt tttgatttgg 6658 ggcatttacc cgaactttgg ttaactgaat ctgttttctt gtctgcttcc tcccctgccc 6718 gctccctgct ctgcccctct gccgtgcgcc tctcctgtgg accaccccac tatgcctggc 6778 ctctggaacg ggtttccag tgg gcg cat cag tta caa tga cat gtt tga gat 6830 Trp Ala His Gln Leu Gln His Val Asp 80 gct gaa aca cat gtc ccc acc tct ggg ttt ggg gaa gaa atg ccc ggc 6878 Ala Glu Thr His Val Pro Thr Ser Gly Phe Gly Glu Glu Met Pro Gly 85 90 95 100 tcg agt tgc ata caa g gtagaccttg accctgcact gatcctgcat ccaacccagg 6934 Ser Ser Cys Ile Gln 105 agctgtctgt gcttggctgg gcccacctgg ccctcattca gcccacagag cactcatggg 6994 ctctcacctg cttccttagg atttgtctgg ctgtctggct gtacctggct gccttactgc 7054 tgctccctca ccaccccgaa atcctttgct cccatcccag acagaggcat acgtctctgc 7114 actaatccac taccctgtct gacttcccca ccactgacat ccttgaggag cttgggacaa 7174 tggagccaga gataccccat ccagggccct tttcccttct ttgcctgtgc tttcccaaga 7234 atgagaagac caacaaaaca atgcttttgg accgagggtg ctttcctcct agatgccctg 7294 cccctgtgct cctgtcatgg gtggtcatca agtctgcaag gtctgcctcc agggacagat 7354 ggggcctgcg ggcctctgct gctcccctgt gccgtgccct tctaccccag ctaagctcag 7414 ccttgtaggg tttgtgccca gctagtcttc aagggcttca aaacttccca gtgggaagga 7474 ggtggggcct tgacgttgga agggaaaggc tgcttggatg ccttggttaa ggctccagct 7534 tcgcattcag gagtcccagc acacgggagt cgtgaggaag gaagtgaaca tggacacctc 7594 caggcctcct tcctggccca gtcatagctc gctgcacctg cagtgccctc agcactcata 7654 gcccctactg ctccccacta aacagtgcca actgtgttag catctgtctg agagctccct 7714 gctggctcct ccctcttcag cccgctgtac tctgtccatc ttctgtctcc gtaccccatt 7774 ctaggttttt ttgtctgcca cttcattcag tgtagtctgt gggaaccaaa cagctctccc 7834 accactcaca gatgcctctg ggttcttcct gcctttatct gcccccaact agcatgtgtg 7894 ttgaaactgc ggaggccttc tgcatgcatg cgtgcatgtc tctacccaca ggagggagag 7954 ctctgttcct atgacaccca gtcagacaga aaggcaggca ggaagggttg cactgccctt 8014 tccagccagg cctgaggatc ctgaggttca gggtgtgacc agaccaagag aggcttcggg 8074 gtaggttgca gatggcttgg ggcaaaatgg gggagggccc aagagatggt tccagtacca 8134 tttctggaac ttatttgcca tggtcttgcc actctgcttc tctgaggttc tatctttctc 8194 tgtcctccat gactgggggc aaacctgtgg gagcccctgt gagggtgacc tttggtgtcc 8254 tggacagatc tccccctctt ggaaacatct gcttgctctt ctctcattcc catcctgacc 8314 cctccctgga agaggaattt cttggcctct cacactgcca tcggtgctgg tctgcaggga 8374 cgccatgctc cgggaagcag gcttttcctg gtgtgtaaca catgtgacac gtgaggtcct 8434 ggtcctgtga ttggacgtgc ccagtggggc tttgccagca ttcagaggac aagagcctac 8494 ctcctgtgtt ctgcacccca tgcccctcta tcacaatgaa gatacagaac gtgggggcaa 8554 gatcctaggg accgggctgt gtggcccttc cctgaagaag ggtgcttgcc ttagggagga 8614 agtcctatct ctagttttct tcctatacag aggacattag tattcctggg gtgcttcatg 8674 gccgactgag tggtntcaga tgcacctgag acctccctca gatgttntga gagccggact 8734 tccttgcagc tgctgagtct acccagagga atgactcaga cacatccctg tttcaagatg 8794 tgttgtctct gaaaaacaag aaaagaaagg gagctggcca ctcagagata taggagcagc 8854 ttgctctgct ctggccctta gaaaggtctc ttaagactct tcttcattca tttacctatg 8914 atggtgtctg tcttcaagtg tgtctccccg gccccctgtt tgtggttaag acctgagtta 8974 agcaagagca tctctcttga tgagtgcctc gttgggactg gacctcagag aggcctcttg 9034 gcttccaccc cttacttacc caatgatcca gttgcagata gagggcaggt aagcaaaaac 9094 cacaggacag ggcctccaac tgtattctaa gctgtcccac tctgccttcc tcagccagga 9154 ccatgccccc ttgtgtcact catagccagt ggtcaggact caggctcctg ggcctggctt 9214 ctgctacagc ttctacttgg acttctgttc ttctctagtc aggagaatct cagcttagat 9274 gagagtaagg tccaggagga gagaatgctg gcaaaacttc caccgcccag ccttctggac 9334 caggcacctg ccaggaccac tctcgggaca ccaagccaag ctccagagcc cagacactaa 9394 ctctagggtg ggagtgaccg taatatgctt ggccctgatc tgcccctcct catccccag 9453 cg cct ggt tcg aat gaa cat gcc cat atc caa tga gga cat gac ggt 9500 Ala Pro Gly Ser Asn Glu His Ala His Ile Gln Gly His Asp Gly 110 115 120 aca ctt tac atc cac act gat ggc cct cat ccg gac ggc act gga gat 9548 Thr Leu Tyr Ile His Thr Asp Gly Pro His Pro Asp Gly Thr Gly Asp 125 130 135 caa gct tgc ccc ag 9562 Gln Ala Cys Pro 140 24 334 DNA Rattus norvegicus 24 atgctgaacc tctttgttgc tgtgatcatg gacaatttcg aatacctcac gcgggattct 60 tccatcctag ggccgcacca cctcgatgaa ttcattcgcg tctgggctga atacgaccca 120 gctgcgtgtt gccggattca ttataaggat atgtacagtt tgttgcgttg tattgcgcca 180 cccgttggct tagggaagaa ctgccctcgt aggttggcct acaagcgcct ggttcgaatg 240 aacatgccca tatccaatga ggacatgacg gtacacttta catccacact gatggccctc 300 atccggacgg cactggagat caagcttgcc ccag 334 25 111 PRT Rattus norvegicus 25 Met Leu Asn Leu Phe Val Ala Val Ile Met Asp Asn Phe Glu Tyr Leu 1 5 10 15 Thr Arg Asp Ser Ser Ile Leu Gly Pro His His Leu Asp Glu Phe Ile 20 25 30 Arg Val Trp Ala Glu Tyr Asp Pro Ala Ala Cys Cys Arg Ile His Tyr 35 40 45 Lys Asp Met Tyr Ser Leu Leu Arg Cys Ile Ala Pro Pro Val Gly Leu 50 55 60 Gly Lys Asn Cys Pro Arg Arg Leu Ala Tyr Lys Arg Leu Val Arg Met 65 70 75 80 Asn Met Pro Ile Ser Asn Glu Asp Met Thr Val His Phe Thr Ser Thr 85 90 95 Leu Met Ala Leu Ile Arg Thr Ala Leu Glu Ile Lys Leu Ala Pro 100 105 110 26 111 PRT Rattus norvegicus 26 Met Leu Asn Leu Phe Val Ala Val Ile Met Asp Asn Phe Glu Tyr Leu 1 5 10 15 Thr Arg Asp Ser Ser Ile Leu Gly Pro His His Leu Asp Glu Phe Ile 20 25 30 Arg Val Trp Ala Glu Tyr Asp Pro Ala Ala Cys Gly Arg Ile Ser Tyr 35 40 45 Asn Asp Met Phe Glu Met Leu Lys His Met Ser Pro Pro Leu Gly Leu 50 55 60 Gly Lys Lys Cys Pro Ala Arg Val Ala Tyr Lys Arg Leu Val Arg Met 65 70 75 80 Asn Met Pro Ile Ser Asn Glu Asp Met Thr Val His Phe Thr Ser Thr 85 90 95 Leu Met Ala Leu Ile Arg Thr Ala Leu Glu Ile Lys Leu Ala Pro 100 105 110 27 9695 DNA Rattus norvegicus CDS (92)..(7093) 27 cggcacgagc ggctaggtta ggagcccctg gcgcgccgcg ccctcggtgc cgggccgcgg 60 agccggggat gcgcgcggcg ccccgggagt c atg gtc cgc ttc ggg gac gag 112 Met Val Arg Phe Gly Asp Glu 1 5 cta ggc ggc cgc tat ggg ggc acc ggc ggc ggg gag cgg gct cgg ggc 160 Leu Gly Gly Arg Tyr Gly Gly Thr Gly Gly Gly Glu Arg Ala Arg Gly 10 15 20 ggc ggg gcc ggc ggg gcc ggt ggc ccg ggc cag ggg ggt ctg ccg ccg 208 Gly Gly Ala Gly Gly Ala Gly Gly Pro Gly Gln Gly Gly Leu Pro Pro 25 30 35 ggc cag cgg gtc ctg tac aag cag tcc att gcg caa cgc gca cgg acc 256 Gly Gln Arg Val Leu Tyr Lys Gln Ser Ile Ala Gln Arg Ala Arg Thr 40 45 50 55 atg gcc ctg tac aac ccc atc cca gtc aag cag aac tgc ttc acc gtc 304 Met Ala Leu Tyr Asn Pro Ile Pro Val Lys Gln Asn Cys Phe Thr Val 60 65 70 aac cgc tcg ctc ttc gtc ttc agc gag gac aac gtc gtc cgc aaa tat 352 Asn Arg Ser Leu Phe Val Phe Ser Glu Asp Asn Val Val Arg Lys Tyr 75 80 85 gct aag cgc atc acc gaa tgg ccg ccc ttc gaa tat atg atc ctg gcc 400 Ala Lys Arg Ile Thr Glu Trp Pro Pro Phe Glu Tyr Met Ile Leu Ala 90 95 100 acc atc atc gcc aac tgt att gtc ctg gcc ctg gag cag cac ctc cct 448 Thr Ile Ile Ala Asn Cys Ile Val Leu Ala Leu Glu Gln His Leu Pro 105 110 115 gat ggg gac aag act ccc atg tct gaa cga ctg gat gac acg gaa cct 496 Asp Gly Asp Lys Thr Pro Met Ser Glu Arg Leu Asp Asp Thr Glu Pro 120 125 130 135 tac ttc atc ggc atc ttt tgc ttc gag gcg ggc atc aag atc ata gct 544 Tyr Phe Ile Gly Ile Phe Cys Phe Glu Ala Gly Ile Lys Ile Ile Ala 140 145 150 ctg ggc ttc gtg ttc cac aaa ggc tcc tac ctc cgg aat ggc tgg aac 592 Leu Gly Phe Val Phe His Lys Gly Ser Tyr Leu Arg Asn Gly Trp Asn 155 160 165 gtc atg gac ttc gtg gtg gtc ctc aca ggg att ctt gcc aca gct gga 640 Val Met Asp Phe Val Val Val Leu Thr Gly Ile Leu Ala Thr Ala Gly 170 175 180 act gac ttt gat ctg cgc acc ctg agg gct gtg cgt gtg ctt agg ccc 688 Thr Asp Phe Asp Leu Arg Thr Leu Arg Ala Val Arg Val Leu Arg Pro 185 190 195 ctg aag ttg gtg tct gga att cca agc ttg cag gtg gtg ctc aag tcc 736 Leu Lys Leu Val Ser Gly Ile Pro Ser Leu Gln Val Val Leu Lys Ser 200 205 210 215 atc atg aag gcc atg gtc ccg ctg ctg cag atc ggg ctg ctg ctc ttc 784 Ile Met Lys Ala Met Val Pro Leu Leu Gln Ile Gly Leu Leu Leu Phe 220 225 230 ttc gcc atc ctc atg ttc gct atc atc ggc ctc gag ttc tat atg ggc 832 Phe Ala Ile Leu Met Phe Ala Ile Ile Gly Leu Glu Phe Tyr Met Gly 235 240 245 aaa ttc cat aag gcc tgc ttc ccc aac agc aca gat gca gag cct gtg 880 Lys Phe His Lys Ala Cys Phe Pro Asn Ser Thr Asp Ala Glu Pro Val 250 255 260 ggt gac ttt cct tgt ggc aag gag gcc cct gct cgt ctg tgt gac agt 928 Gly Asp Phe Pro Cys Gly Lys Glu Ala Pro Ala Arg Leu Cys Asp Ser 265 270 275 gac acc gaa tgc cgg gag tac tgg cca gga ccc aac ttt ggc atc acc 976 Asp Thr Glu Cys Arg Glu Tyr Trp Pro Gly Pro Asn Phe Gly Ile Thr 280 285 290 295 aat ttt gac aac atc ctg ttt gcc atc ttg acc gtg ttc cag tgt atc 1024 Asn Phe Asp Asn Ile Leu Phe Ala Ile Leu Thr Val Phe Gln Cys Ile 300 305 310 acc atg gag ggc tgg act gac atc ctc tac aat aca aat gat gcg gcc 1072 Thr Met Glu Gly Trp Thr Asp Ile Leu Tyr Asn Thr Asn Asp Ala Ala 315 320 325 ggc aac acg tgg aac tgg ttg tac ttc atc ccc ctc atc atc att ggc 1120 Gly Asn Thr Trp Asn Trp Leu Tyr Phe Ile Pro Leu Ile Ile Ile Gly 330 335 340 tcc ttc ttc atg ctc aac ctg gtg ctc ggt gtg ctt tca gga gag ttt 1168 Ser Phe Phe Met Leu Asn Leu Val Leu Gly Val Leu Ser Gly Glu Phe 345 350 355 gcc aaa gag cgg gag cga gtc gag aac cgc cgt gcc ttc ctg aag ctc 1216 Ala Lys Glu Arg Glu Arg Val Glu Asn Arg Arg Ala Phe Leu Lys Leu 360 365 370 375 cgc agg cag cag cag att gag cga gaa ctg aat ggg tac ttg gag tgg 1264 Arg Arg Gln Gln Gln Ile Glu Arg Glu Leu Asn Gly Tyr Leu Glu Trp 380 385 390 atc ttc aag gcg gag gaa gtc atg ttg gca gag gag gac aag aac gca 1312 Ile Phe Lys Ala Glu Glu Val Met Leu Ala Glu Glu Asp Lys Asn Ala 395 400 405 gaa gag aag tcc cct ttg gat gtg ttg aag aga gct gct acc aag aag 1360 Glu Glu Lys Ser Pro Leu Asp Val Leu Lys Arg Ala Ala Thr Lys Lys 410 415 420 agc cga aat gac ctc atc cat gca gaa gag ggg gag gac cgg ttt gta 1408 Ser Arg Asn Asp Leu Ile His Ala Glu Glu Gly Glu Asp Arg Phe Val 425 430 435 gac ctc tgt gct gct ggg tct ccc ttt gct cgt gcc agc ctc aag agt 1456 Asp Leu Cys Ala Ala Gly Ser Pro Phe Ala Arg Ala Ser Leu Lys Ser 440 445 450 455 ggg aag aca gag agc tca tcg tac ttc cgg agg aag gag aag atg ttc 1504 Gly Lys Thr Glu Ser Ser Ser Tyr Phe Arg Arg Lys Glu Lys Met Phe 460 465 470 cgg ttc ctt atc cgt cgt atg gtg aaa gca cag agc ttc tac tgg gtg 1552 Arg Phe Leu Ile Arg Arg Met Val Lys Ala Gln Ser Phe Tyr Trp Val 475 480 485 gta ctg tgc gtg gtg gcc ctg aac acg ttg tgt gtg gcc atg gta cac 1600 Val Leu Cys Val Val Ala Leu Asn Thr Leu Cys Val Ala Met Val His 490 495 500 tat aat cag cct cag cgg ctt acc act gca ctg tac ttt gca gag ttt 1648 Tyr Asn Gln Pro Gln Arg Leu Thr Thr Ala Leu Tyr Phe Ala Glu Phe 505 510 515 gtt ttc ctg ggt ctc ttc ctc aca gag atg tcc ctg aag atg tac ggt 1696 Val Phe Leu Gly Leu Phe Leu Thr Glu Met Ser Leu Lys Met Tyr Gly 520 525 530 535 cta ggg ccc aga agc tac ttc cgg tct tcc ttc aac tgc ttt gac ttt 1744 Leu Gly Pro Arg Ser Tyr Phe Arg Ser Ser Phe Asn Cys Phe Asp Phe 540 545 550 ggg gtg att gtg ggg agt atc ttt gaa gta gtc tgg gct gcc atc aag 1792 Gly Val Ile Val Gly Ser Ile Phe Glu Val Val Trp Ala Ala Ile Lys 555 560 565 cca gga acc tcc ttc gga atc agt gtg ctg cgg gct ctc cga ctg ctg 1840 Pro Gly Thr Ser Phe Gly Ile Ser Val Leu Arg Ala Leu Arg Leu Leu 570 575 580 agg att ttc aaa gtc acc aag tat tgg aac tcc ctg agg aac ctg gtt 1888 Arg Ile Phe Lys Val Thr Lys Tyr Trp Asn Ser Leu Arg Asn Leu Val 585 590 595 gtt tcc ctc ctc aac tcc atg aag tcc atc atc agc ctt ctc ttc ctg 1936 Val Ser Leu Leu Asn Ser Met Lys Ser Ile Ile Ser Leu Leu Phe Leu 600 605 610 615 ctt ttc ctt ttc att gtg gtc ttc gct ctg ttg ggg atg cag ctg ttt 1984 Leu Phe Leu Phe Ile Val Val Phe Ala Leu Leu Gly Met Gln Leu Phe 620 625 630 ggg gga cag ttc aac ttt caa gat gag act cca acc acc aat ttt gat 2032 Gly Gly Gln Phe Asn Phe Gln Asp Glu Thr Pro Thr Thr Asn Phe Asp 635 640 645 acc ttc cca gct gcc atc ctc act gtg ttt cag att ctg aca gga gag 2080 Thr Phe Pro Ala Ala Ile Leu Thr Val Phe Gln Ile Leu Thr Gly Glu 650 655 660 gac tgg aat gca gtc atg tat cat ggg att gag tca caa gga gga gtc 2128 Asp Trp Asn Ala Val Met Tyr His Gly Ile Glu Ser Gln Gly Gly Val 665 670 675 agc aaa ggc atg ttt tca tcc ttt tac ttc atc gtc ctg aca ctg ttt 2176 Ser Lys Gly Met Phe Ser Ser Phe Tyr Phe Ile Val Leu Thr Leu Phe 680 685 690 695 gga aac tac acc ctg ttg aac gtt ttc ttg gcc att gct gtg gac aac 2224 Gly Asn Tyr Thr Leu Leu Asn Val Phe Leu Ala Ile Ala Val Asp Asn 700 705 710 ctt gcc aat gcc cag gag ttg acc aag gat gaa gag gag atg gaa gag 2272 Leu Ala Asn Ala Gln Glu Leu Thr Lys Asp Glu Glu Glu Met Glu Glu 715 720 725 gca gcc aat cag aag ctt gct ctt cag aag gcc aaa gaa gta gct gaa 2320 Ala Ala Asn Gln Lys Leu Ala Leu Gln Lys Ala Lys Glu Val Ala Glu 730 735 740 gtc agc ccc atg tct gct gcc aac atc tcc att gct gcc agg cag cag 2368 Val Ser Pro Met Ser Ala Ala Asn Ile Ser Ile Ala Ala Arg Gln Gln 745 750 755 aac tcg gcc aag gcg cgc tca gta tgg gag cag cgg gcc agt cag cta 2416 Asn Ser Ala Lys Ala Arg Ser Val Trp Glu Gln Arg Ala Ser Gln Leu 760 765 770 775 agg ctc cag aac ctg cgt gcc agc tgt gag gca ctg tac agt gag atg 2464 Arg Leu Gln Asn Leu Arg Ala Ser Cys Glu Ala Leu Tyr Ser Glu Met 780 785 790 gac ccg gag gag cgc ctg cgt tat gcc agc acg cgc cac gtg agg cca 2512 Asp Pro Glu Glu Arg Leu Arg Tyr Ala Ser Thr Arg His Val Arg Pro 795 800 805 gac atg aag aca cac atg gac cga ccc cta gtg gtg gaa cct ggt cgg 2560 Asp Met Lys Thr His Met Asp Arg Pro Leu Val Val Glu Pro Gly Arg 810 815 820 gat ggc ctg cgg gga ccc gcc ggg aac aag tca aag cct gag ggc acg 2608 Asp Gly Leu Arg Gly Pro Ala Gly Asn Lys Ser Lys Pro Glu Gly Thr 825 830 835 gag gcc acc gaa ggt gcg gat cca cca cgc cga cac cac cgg cat cgt 2656 Glu Ala Thr Glu Gly Ala Asp Pro Pro Arg Arg His His Arg His Arg 840 845 850 855 gat agg gac aag acc tca gcc tca acc cct gct gga ggc gaa cag gac 2704 Asp Arg Asp Lys Thr Ser Ala Ser Thr Pro Ala Gly Gly Glu Gln Asp 860 865 870 agg aca gac tgc cca aag gcc gaa agc acc gag acc ggg gcc cgg gag 2752 Arg Thr Asp Cys Pro Lys Ala Glu Ser Thr Glu Thr Gly Ala Arg Glu 875 880 885 gaa cgt gcg cgc cct cgt cga agt cac agc aag gag gct cca ggg gct 2800 Glu Arg Ala Arg Pro Arg Arg Ser His Ser Lys Glu Ala Pro Gly Ala 890 895 900 gac aca caa gtg cgt tgt gag cgc agt aga cgt cac cac cgg cgc gga 2848 Asp Thr Gln Val Arg Cys Glu Arg Ser Arg Arg His His Arg Arg Gly 905 910 915 tcc ccg gag gag gcc act gaa cgg gaa cct cgg cgc cac cgt gcc cac 2896 Ser Pro Glu Glu Ala Thr Glu Arg Glu Pro Arg Arg His Arg Ala His 920 925 930 935 cgg cac gca cag gac tca agc aag gaa ggc aag gag ggc act gca ccg 2944 Arg His Ala Gln Asp Ser Ser Lys Glu Gly Lys Glu Gly Thr Ala Pro 940 945 950 gtg ctt gta ccc aag ggc gag cgt cgc gca aga cat cga ggc ccg cgt 2992 Val Leu Val Pro Lys Gly Glu Arg Arg Ala Arg His Arg Gly Pro Arg 955 960 965 acg ggc ccc cgt gag aca gag aac agt gag gag ccc aca cgc agg cac 3040 Thr Gly Pro Arg Glu Thr Glu Asn Ser Glu Glu Pro Thr Arg Arg His 970 975 980 cgt gca aag cat aag gtg cca cca aca ctt gag ccc cca gag agg gag 3088 Arg Ala Lys His Lys Val Pro Pro Thr Leu Glu Pro Pro Glu Arg Glu 985 990 995 gtt gca gag aag gag agc aac gtg gtg gaa ggg gat aag gaa act 3133 Val Ala Glu Lys Glu Ser Asn Val Val Glu Gly Asp Lys Glu Thr 1000 1005 1010 cga aat cac cag ccc aag gaa cct cgc tgt gac ctg gag gcc att 3178 Arg Asn His Gln Pro Lys Glu Pro Arg Cys Asp Leu Glu Ala Ile 1015 1020 1025 gcg gtt aca ggc gtg ggc tct ctg cac atg ctg ccc agc acc tgt 3223 Ala Val Thr Gly Val Gly Ser Leu His Met Leu Pro Ser Thr Cys 1030 1035 1040 ctc cag aaa gtg gac gaa cag cca gag gat gca gac aac cag cgt 3268 Leu Gln Lys Val Asp Glu Gln Pro Glu Asp Ala Asp Asn Gln Arg 1045 1050 1055 aat gtc acc cgg atg ggc agt cag ccc tca gac ccc agc acc act 3313 Asn Val Thr Arg Met Gly Ser Gln Pro Ser Asp Pro Ser Thr Thr 1060 1065 1070 gtg cat gtc cca gtg aca ctg aca ggc cct ccc ggg gag gcc act 3358 Val His Val Pro Val Thr Leu Thr Gly Pro Pro Gly Glu Ala Thr 1075 1080 1085 gta gtt ccc agt gct aac acg gac ctg gaa ggc caa gcg gag ggc 3403 Val Val Pro Ser Ala Asn Thr Asp Leu Glu Gly Gln Ala Glu Gly 1090 1095 1100 aag aag gag gca gag gct gac gat gtg ctg aga aga ggc ccc agg 3448 Lys Lys Glu Ala Glu Ala Asp Asp Val Leu Arg Arg Gly Pro Arg 1105 1110 1115 ccc atc gtt ccc tac agt tcc atg ttc tgc ctc agc ccc acc aac 3493 Pro Ile Val Pro Tyr Ser Ser Met Phe Cys Leu Ser Pro Thr Asn 1120 1125 1130 cta ctc cgt cgc ttc tgc cat tac att gtg acc atg cgg tac ttt 3538 Leu Leu Arg Arg Phe Cys His Tyr Ile Val Thr Met Arg Tyr Phe 1135 1140 1145 gag atg gtg att ctt gtg gtc atc gcc ttg agc agc att gcc ctg 3583 Glu Met Val Ile Leu Val Val Ile Ala Leu Ser Ser Ile Ala Leu 1150 1155 1160 gct gct gag gat ccc gtg cgg acc gac tca ttc cgg aac aat gct 3628 Ala Ala Glu Asp Pro Val Arg Thr Asp Ser Phe Arg Asn Asn Ala 1165 1170 1175 ctg aag tac atg gac tac atc ttt aca gga gtc ttc acc ttt gag 3673 Leu Lys Tyr Met Asp Tyr Ile Phe Thr Gly Val Phe Thr Phe Glu 1180 1185 1190 atg gtc ata aag atg ata gac ttg ggc ctg ctg ctg cac cct ggg 3718 Met Val Ile Lys Met Ile Asp Leu Gly Leu Leu Leu His Pro Gly 1195 1200 1205 gcc tac ttc cgg gac ctg tgg aac att ctg gac ttc att gtt gtc 3763 Ala Tyr Phe Arg Asp Leu Trp Asn Ile Leu Asp Phe Ile Val Val 1210 1215 1220 agt gga gcc ctg gtg gca ttt gca ttc tca gga tcc aaa ggg aaa 3808 Ser Gly Ala Leu Val Ala Phe Ala Phe Ser Gly Ser Lys Gly Lys 1225 1230 1235 gac atc aat acc atc aag tct ctg aga gtc ctg cga gtc ctg cgg 3853 Asp Ile Asn Thr Ile Lys Ser Leu Arg Val Leu Arg Val Leu Arg 1240 1245 1250 ccc ctc aag acc atc aag cgg ctg cct aaa ctc aag gct gtg ttt 3898 Pro Leu Lys Thr Ile Lys Arg Leu Pro Lys Leu Lys Ala Val Phe 1255 1260 1265 gac tgt gtg gtg aac tct ctg aag aat gtc ttg aac atc ctg atc 3943 Asp Cys Val Val Asn Ser Leu Lys Asn Val Leu Asn Ile Leu Ile 1270 1275 1280 gtc tac atg ctc ttc atg ttt ata ttt gcc gtc atc gcc gtc caa 3988 Val Tyr Met Leu Phe Met Phe Ile Phe Ala Val Ile Ala Val Gln 1285 1290 1295 ctc ttc aaa ggg aag ttc ttt tac tgc act gat gag tcc aag gag 4033 Leu Phe Lys Gly Lys Phe Phe Tyr Cys Thr Asp Glu Ser Lys Glu 1300 1305 1310 ctg gag cgg gac tgc agg ggt cag tat ttg gat tat gag aag gaa 4078 Leu Glu Arg Asp Cys Arg Gly Gln Tyr Leu Asp Tyr Glu Lys Glu 1315 1320 1325 gag gta gaa gcc cag cca agg cag tgg aag aaa tat gac ttc cac 4123 Glu Val Glu Ala Gln Pro Arg Gln Trp Lys Lys Tyr Asp Phe His 1330 1335 1340 tat gac aat gtg ctc tgg gcc ttg ctg act ctg ttt acg gtg tcc 4168 Tyr Asp Asn Val Leu Trp Ala Leu Leu Thr Leu Phe Thr Val Ser 1345 1350 1355 aca gga gag ggg tgg ccc atg gtg ctg aaa cac tct gtg gac gcc 4213 Thr Gly Glu Gly Trp Pro Met Val Leu Lys His Ser Val Asp Ala 1360 1365 1370 acc tat gag gag cag ggg cca agc ccc ggg ttt cgg atg gag ctt 4258 Thr Tyr Glu Glu Gln Gly Pro Ser Pro Gly Phe Arg Met Glu Leu 1375 1380 1385 tcc atc ttc tat gtg gtc tac ttt gtg gtc ttc cct ttt ttc ttt 4303 Ser Ile Phe Tyr Val Val Tyr Phe Val Val Phe Pro Phe Phe Phe 1390 1395 1400 gtc aac atc ttt gtg gcc ttg atc atc atc acc ttc cag gag cag 4348 Val Asn Ile Phe Val Ala Leu Ile Ile Ile Thr Phe Gln Glu Gln 1405 1410 1415 ggg gac aag gtg atg tct gag tgc agt ctg gaa aag aat gag agg 4393 Gly Asp Lys Val Met Ser Glu Cys Ser Leu Glu Lys Asn Glu Arg 1420 1425 1430 gct tgc att gac ttt gcc atc agc gcc aaa ccc ctg aca cgg tac 4438 Ala Cys Ile Asp Phe Ala Ile Ser Ala Lys Pro Leu Thr Arg Tyr 1435 1440 1445 atg cct cag aac aag cag tcg ttc cag tat aag aca tgg aca ttt 4483 Met Pro Gln Asn Lys Gln Ser Phe Gln Tyr Lys Thr Trp Thr Phe 1450 1455 1460 gtg gtc tct cca ccc ttt gag tac ttc att atg gcc atg ata gcc 4528 Val Val Ser Pro Pro Phe Glu Tyr Phe Ile Met Ala Met Ile Ala 1465 1470 1475 ctc aac aca gtg gtg ctg atg atg aag ttc tac gat gcc cct tat 4573 Leu Asn Thr Val Val Leu Met Met Lys Phe Tyr Asp Ala Pro Tyr 1480 1485 1490 gag tac gag ctg atg ctg aag tgc ttg aac atc gtc ttc aca tcc 4618 Glu Tyr Glu Leu Met Leu Lys Cys Leu Asn Ile Val Phe Thr Ser 1495 1500 1505 atg ttc tct ctg gag tgc atc ctg aag atc atc gcc ttc ggg gtg 4663 Met Phe Ser Leu Glu Cys Ile Leu Lys Ile Ile Ala Phe Gly Val 1510 1515 1520 ttg aac tac ttc aga gat gcc tgg aac gtc ttt gac ttt gtc act 4708 Leu Asn Tyr Phe Arg Asp Ala Trp Asn Val Phe Asp Phe Val Thr 1525 1530 1535 gtt ttg gga agt att act gat att tta gta acg gag att gcg gaa 4753 Val Leu Gly Ser Ile Thr Asp Ile Leu Val Thr Glu Ile Ala Glu 1540 1545 1550 acg aac aac ttc atc aac ttg agc ttc ctt cgc ctc ttc cgg gca 4798 Thr Asn Asn Phe Ile Asn Leu Ser Phe Leu Arg Leu Phe Arg Ala 1555 1560 1565 gca cgg ctg atc aag ctg ctt cgc cag ggc tac acc atc cgc atc 4843 Ala Arg Leu Ile Lys Leu Leu Arg Gln Gly Tyr Thr Ile Arg Ile 1570 1575 1580 ttg tta tgg acc ttt gtc cag tcc ttt aag gcg ctg ccc tac gtg 4888 Leu Leu Trp Thr Phe Val Gln Ser Phe Lys Ala Leu Pro Tyr Val 1585 1590 1595 tgc ctc ctc att gcc atg ctg ttc ttc atc tac gcc atc atc ggc 4933 Cys Leu Leu Ile Ala Met Leu Phe Phe Ile Tyr Ala Ile Ile Gly 1600 1605 1610 atg cag gtt ttt gga aac att gcc ctt gat gat ggc acc agc atc 4978 Met Gln Val Phe Gly Asn Ile Ala Leu Asp Asp Gly Thr Ser Ile 1615 1620 1625 aac cga cac aac aac ttc cgg aca ttt ctg caa gcc tta atg ctg 5023 Asn Arg His Asn Asn Phe Arg Thr Phe Leu Gln Ala Leu Met Leu 1630 1635 1640 ttg ttc agg agt gcc act ggg gag gcc tgg cac gaa atc atg ctg 5068 Leu Phe Arg Ser Ala Thr Gly Glu Ala Trp His Glu Ile Met Leu 1645 1650 1655 tct tgc ctg ggc aac cgg gcc tgc gac cca cat gcc aac gcc agc 5113 Ser Cys Leu Gly Asn Arg Ala Cys Asp Pro His Ala Asn Ala Ser 1660 1665 1670 gaa tgc ggg agc gac ttt gcc tat ttt tat ttt gtc tcc ttc atc 5158 Glu Cys Gly Ser Asp Phe Ala Tyr Phe Tyr Phe Val Ser Phe Ile 1675 1680 1685 ttc ctc tgt tcc ttt ctg atg ctg aac ctc ttt gtt gct gtg atc 5203 Phe Leu Cys Ser Phe Leu Met Leu Asn Leu Phe Val Ala Val Ile 1690 1695 1700 atg gac aat ttc gaa tac ctc acg cgg gat tct tcc atc cta ggg 5248 Met Asp Asn Phe Glu Tyr Leu Thr Arg Asp Ser Ser Ile Leu Gly 1705 1710 1715 ccg cac cac ctc gat gaa ttc att cgc gtc tgg gct gaa tac gac 5293 Pro His His Leu Asp Glu Phe Ile Arg Val Trp Ala Glu Tyr Asp 1720 1725 1730 cca gct gcg tgt ggg cgc atc agt tac aat gac atg ttt gag atg 5338 Pro Ala Ala Cys Gly Arg Ile Ser Tyr Asn Asp Met Phe Glu Met 1735 1740 1745 ctg aaa cac atg tcc cca cct ctg ggt ttg ggg aag aaa tgc ccg 5383 Leu Lys His Met Ser Pro Pro Leu Gly Leu Gly Lys Lys Cys Pro 1750 1755 1760 gct cga gtt gca tac aag cgc ctg gtt cga atg aac atg ccc ata 5428 Ala Arg Val Ala Tyr Lys Arg Leu Val Arg Met Asn Met Pro Ile 1765 1770 1775 tcc aat gag gac atg acg gta cac ttt aca tcc aca ctg atg gcc 5473 Ser Asn Glu Asp Met Thr Val His Phe Thr Ser Thr Leu Met Ala 1780 1785 1790 ctc atc cgg acg gca ctg gag atc aag ctt gcc cca gcg ggg aca 5518 Leu Ile Arg Thr Ala Leu Glu Ile Lys Leu Ala Pro Ala Gly Thr 1795 1800 1805 aaa cag cac caa tgt gat gct gag ctg agg aag gag atc tct tct 5563 Lys Gln His Gln Cys Asp Ala Glu Leu Arg Lys Glu Ile Ser Ser 1810 1815 1820 gtg tgg gct aat ctg ccc cag aag act ctg gac tta ctg gtg cca 5608 Val Trp Ala Asn Leu Pro Gln Lys Thr Leu Asp Leu Leu Val Pro 1825 1830 1835 ccc cac aaa cct gac gag atg aca gtg ggg aag gtc tat gcg gct 5653 Pro His Lys Pro Asp Glu Met Thr Val Gly Lys Val Tyr Ala Ala 1840 1845 1850 ctc atg ata ttt gac ttc tac aaa cag aac aaa acc acc aga gat 5698 Leu Met Ile Phe Asp Phe Tyr Lys Gln Asn Lys Thr Thr Arg Asp 1855 1860 1865 cag act cac caa gct cct gga ggc ctg tcc cag atg ggt cct gtt 5743 Gln Thr His Gln Ala Pro Gly Gly Leu Ser Gln Met Gly Pro Val 1870 1875 1880 tcc ctg ttc cat cct ctg aag gcc acc ctg gag cag aca cag ccc 5788 Ser Leu Phe His Pro Leu Lys Ala Thr Leu Glu Gln Thr Gln Pro 1885 1890 1895 gct gtg ctc cga gga gct cgg gtt ttc ctt cga caa aag agt gca 5833 Ala Val Leu Arg Gly Ala Arg Val Phe Leu Arg Gln Lys Ser Ala 1900 1905 1910 act tcc ctc agc aat ggg ggc gcc ata caa acc cag gaa agt ggc 5878 Thr Ser Leu Ser Asn Gly Gly Ala Ile Gln Thr Gln Glu Ser Gly 1915 1920 1925 atc aag gag tcc ctg tcc tgg ggc acg cag agg acc cag gac gta 5923 Ile Lys Glu Ser Leu Ser Trp Gly Thr Gln Arg Thr Gln Asp Val 1930 1935 1940 ctt tat gag gcc aga gca cct cta gaa cgt ggc cat tct gca gag 5968 Leu Tyr Glu Ala Arg Ala Pro Leu Glu Arg Gly His Ser Ala Glu 1945 1950 1955 atc cct gtg ggg cag cca gga gca ctg gct gta gat gtc cag atg 6013 Ile Pro Val Gly Gln Pro Gly Ala Leu Ala Val Asp Val Gln Met 1960 1965 1970 cag aac atg aca ttg aga gga ccg gat ggg gag ccc cag cct ggc 6058 Gln Asn Met Thr Leu Arg Gly Pro Asp Gly Glu Pro Gln Pro Gly 1975 1980 1985 ctg gag agc caa ggc cga gcg gcc tct atg cca cgc ctg gcg gca 6103 Leu Glu Ser Gln Gly Arg Ala Ala Ser Met Pro Arg Leu Ala Ala 1990 1995 2000 gaa aca cag ccg gcc cct aat gcc agc ccc atg aag cgc tcc atc 6148 Glu Thr Gln Pro Ala Pro Asn Ala Ser Pro Met Lys Arg Ser Ile 2005 2010 2015 tcc aca ctg gct cca cgc ccg cat ggg act cag ctt tgc aac aca 6193 Ser Thr Leu Ala Pro Arg Pro His Gly Thr Gln Leu Cys Asn Thr 2020 2025 2030 gtc ctg gac cgg cca cct cct agc cag gtg tcc cat cac cac cac 6238 Val Leu Asp Arg Pro Pro Pro Ser Gln Val Ser His His His His 2035 2040 2045 cac cgc tgc cac cgg cgc agg gac aag aag cag agg tcc ctg gaa 6283 His Arg Cys His Arg Arg Arg Asp Lys Lys Gln Arg Ser Leu Glu 2050 2055 2060 aag ggg ccc agc ctg tct gtt gac aca gaa ggt gca cca agt act 6328 Lys Gly Pro Ser Leu Ser Val Asp Thr Glu Gly Ala Pro Ser Thr 2065 2070 2075 gct gca gga tct ggc ctg ccc cat gga gaa ggg tcc aca ggc tgc 6373 Ala Ala Gly Ser Gly Leu Pro His Gly Glu Gly Ser Thr Gly Cys 2080 2085 2090 cgg cgg gag cgt aag caa gag cga ggc cgg tcc cag gag cgg agg 6418 Arg Arg Glu Arg Lys Gln Glu Arg Gly Arg Ser Gln Glu Arg Arg 2095 2100 2105 cag ccc tcc tcc tct tct tca gag aag cag cgc ttc tat tcc tgt 6463 Gln Pro Ser Ser Ser Ser Ser Glu Lys Gln Arg Phe Tyr Ser Cys 2110 2115 2120 gac cgc ttt ggg agc cgg gag ccc cca caa cct aag ccc tcc ctc 6508 Asp Arg Phe Gly Ser Arg Glu Pro Pro Gln Pro Lys Pro Ser Leu 2125 2130 2135 agt agc cac ccc ata tcg cca aca gcg gca cta gag cca gga ccc 6553 Ser Ser His Pro Ile Ser Pro Thr Ala Ala Leu Glu Pro Gly Pro 2140 2145 2150 cac ccg cag ggc agt ggt tcc gtt aat ggg agc ccc ttg atg tca 6598 His Pro Gln Gly Ser Gly Ser Val Asn Gly Ser Pro Leu Met Ser 2155 2160 2165 aca tct ggt gct agc acg ccg ggc cga ggt ggg cgg agg cag ctc 6643 Thr Ser Gly Ala Ser Thr Pro Gly Arg Gly Gly Arg Arg Gln Leu 2170 2175 2180 ccc cag act ccc ctg acc cca cgc ccc agc atc acc tac aag acg 6688 Pro Gln Thr Pro Leu Thr Pro Arg Pro Ser Ile Thr Tyr Lys Thr 2185 2190 2195 gcc aat tcc tcg cct gtc cac ttt gct gag ggt cag agt ggc ctt 6733 Ala Asn Ser Ser Pro Val His Phe Ala Glu Gly Gln Ser Gly Leu 2200 2205 2210 cca gcc ttc tcc cct ggc cgt ctc agc cgc ggc ctt tct gaa cac 6778 Pro Ala Phe Ser Pro Gly Arg Leu Ser Arg Gly Leu Ser Glu His 2215 2220 2225 aat gcc ctg ctc cag aaa gag ccc ctg agc cag cct cta gct tct 6823 Asn Ala Leu Leu Gln Lys Glu Pro Leu Ser Gln Pro Leu Ala Ser 2230 2235 2240 ggc tcc cgc att ggc tct gac cct tac cta ggg cag cgt ctg gac 6868 Gly Ser Arg Ile Gly Ser Asp Pro Tyr Leu Gly Gln Arg Leu Asp 2245 2250 2255 agt gag gcc tct gcc cac aac ctg cct gag gat aca ctc acc ttt 6913 Ser Glu Ala Ser Ala His Asn Leu Pro Glu Asp Thr Leu Thr Phe 2260 2265 2270 gaa gag gcc gtg gcc acc aac tct ggc cgc tcc tcc agg act tcc 6958 Glu Glu Ala Val Ala Thr Asn Ser Gly Arg Ser Ser Arg Thr Ser 2275 2280 2285 tat gtg tcc tcc ctc act tcc caa tcc cac cct ctc cgc cgt gta 7003 Tyr Val Ser Ser Leu Thr Ser Gln Ser His Pro Leu Arg Arg Val 2290 2295 2300 ccc aat ggc tac cac tgc act ttg gga ctc agc acc ggc gtc cgg 7048 Pro Asn Gly Tyr His Cys Thr Leu Gly Leu Ser Thr Gly Val Arg 2305 2310 2315 gcg cgg cac agc tac cac cac cca gac cag gat cac tgg tgc tag 7093 Ala Arg His Ser Tyr His His Pro Asp Gln Asp His Trp Cys 2320 2325 2330 ctgcaccacg accacccatg caccagctcg tgggtgcggg ttccagttga tgagttttat 7153 catccgctct gggttgtgcg gtcacagccc tgggaggagg gtcctcacat cgcggcctct 7213 gtggtggagg ttcctgcttc tctccctccc tcccttttac actggacaga ctaataaagc 7273 cctttcttag agggatatgg tcctctctat cctcctgtgt actgccttcc tgggttccat 7333 gccagatgtt ggatcctaag cagaggtagc tgagttgaga tagacccagc aaatccaaat 7393 cctatgtcat ggcctccagc ttccagggtg ggtacttggg actttcttag gaggtctgag 7453 cctcatggag attgtggttt gtccaaatgt gtggcatggg ggatagggta ccctcaaagg 7513 caaggaaagg agcccaactg tgtggcctgg cagcacctgc cagcatcact actctcatgt 7573 ctattgtggt cttggagtca aacagcacat gtatatagag atatgctcaa gggcctgcct 7633 ttcacctaca ttgtcaccat aatagggacc aaatctagag gatgtccttg ctgttgattc 7693 tggttttcag tcacaacact ttcacttttt gtcatttcta tatagttgat ctagaaaaac 7753 agaaatcaaa acagggaaga aaatgttcgt gtaacttaaa aaagaaatca acgtgtagga 7813 aggtctccat tttgcattgt ttctgtgact tgtatgcaat gttcctgtat gtattctacc 7873 cttcccggga agtccccaat gaccctggtt cctctgctca accaagtgcc tgatctctgg 7933 ctctgagcat cgtggctgag gtgcggcctc aggaagcatc ggggagctgc tcagagcagc 7993 actaggactt gtgtcttagg gacactgacc gtgtccagca gcatgtcaga gaagcagctg 8053 tagtgcccat gttcctccct gagtgatggg ttctgaagaa gccagagcag cacaatgtgt 8113 gcttgcgtga ggcactttcc gccttttaaa atctgattct cagggatggg atgcctgcca 8173 agtagggtgt gatctctgtt gtgttttaaa aaacaacaac aacaaacaaa caaaacctag 8233 tattcactga atgctgaaga gagcaaaatg caagcaaaga agggactggg gttagaggga 8293 gaagcccgca ctggcagcat aataagaaac tggcagggag gggatggtcc tggaacaggc 8353 caggtgccta gagctgagtc cagcccctgg cccggaactg gggacacagc actcaaataa 8413 aacctcatgg ctacttggtg aaaggcaaac ccatgctcag gaaggtgttc agtgtgcaga 8473 gatggctgtg aggccatgag agaaaggttt cacataggca ggcagtcctt ggtgtgttct 8533 ctgtgttttg aaacgtctga tgacttcttg gtggactgtt ggtttctacc ccatgtttct 8593 cacagaagct gtgtatatgt gtgattgcgc gtgtgattgc atgtgtgtgg tagtgtgcgt 8653 gcgtgagcat gcatgagtca taggaaatgt gtgtgtgtgt gtgtgtgtgt gtgtaggtgt 8713 gtgtacgtgt gttcagcaag tggcttttgt caaccatagg gctatgcaac aaaagacaca 8773 ttactagaaa caaaacacaa gaccaccact cggtctaggg tttcagcatg attgtgacca 8833 aaccttttat agaatttcct tatatgaagg cacaataccc tgaaacttta aagataacag 8893 agtattttat tccagtaggg taagattaaa caggaccctg gactgcatgt gactgcactc 8953 atgtacaaca gaggaggatg tgcattttga tactgttctg tctctgtccc agccccagcc 9013 cttttctctt gagtgttgaa tgtatacatt ctgtgtggaa ctacagctgc tccagacagt 9073 cctgggttgg gaatcatctt tatcccacat taacatagct ggcttttctt ccaagcactg 9133 gtacacagga aaggagacat gatgtcttgc ttcctgactt tgggtttgtt tctgtactgt 9193 ctcttctcaa gatgttgtct gttccccctg aaatttcata gtgagttgcc aaatttgaaa 9253 tgcaacaacc agctgtctgc atctggaacc tgtcaagcag tgctgtagtt tgaaaaagtt 9313 atgtgtgcat gtaaaatata cacatatata tatatacatt atacaagtat gtgcatgaaa 9373 tgtatatctt catacttttt gatacaatgt attcatttgt taatttttaa ttatatttga 9433 tataaattga aggtttgttg caaaaattta tatttaacag tgttgagaga gagagaaaga 9493 gcgagagagg gagagagaga gaaagatcca atcatgcaac agaaatggga ctactttaaa 9553 aatcagtcct ttgactagtt tgctgccctg aataatattt acaaaccaaa ctttggattc 9613 tgctcttgtt tctacaatga ctttttgtat aaagcaaagt ccttggatta ataaaacaac 9673 caaaaatcaa attaaaccat ta 9695 28 2333 PRT Rattus norvegicus 28 Met Val Arg Phe Gly Asp Glu Leu Gly Gly Arg Tyr Gly Gly Thr Gly 1 5 10 15 Gly Gly Glu Arg Ala Arg Gly Gly Gly Ala Gly Gly Ala Gly Gly Pro 20 25 30 Gly Gln Gly Gly Leu Pro Pro Gly Gln Arg Val Leu Tyr Lys Gln Ser 35 40 45 Ile Ala Gln Arg Ala Arg Thr Met Ala Leu Tyr Asn Pro Ile Pro Val 50 55 60 Lys Gln Asn Cys Phe Thr Val Asn Arg Ser Leu Phe Val Phe Ser Glu 65 70 75 80 Asp Asn Val Val Arg Lys Tyr Ala Lys Arg Ile Thr Glu Trp Pro Pro 85 90 95 Phe Glu Tyr Met Ile Leu Ala Thr Ile Ile Ala Asn Cys Ile Val Leu 100 105 110 Ala Leu Glu Gln His Leu Pro Asp Gly Asp Lys Thr Pro Met Ser Glu 115 120 125 Arg Leu Asp Asp Thr Glu Pro Tyr Phe Ile Gly Ile Phe Cys Phe Glu 130 135 140 Ala Gly Ile Lys Ile Ile Ala Leu Gly Phe Val Phe His Lys Gly Ser 145 150 155 160 Tyr Leu Arg Asn Gly Trp Asn Val Met Asp Phe Val Val Val Leu Thr 165 170 175 Gly Ile Leu Ala Thr Ala Gly Thr Asp Phe Asp Leu Arg Thr Leu Arg 180 185 190 Ala Val Arg Val Leu Arg Pro Leu Lys Leu Val Ser Gly Ile Pro Ser 195 200 205 Leu Gln Val Val Leu Lys Ser Ile Met Lys Ala Met Val Pro Leu Leu 210 215 220 Gln Ile Gly Leu Leu Leu Phe Phe Ala Ile Leu Met Phe Ala Ile Ile 225 230 235 240 Gly Leu Glu Phe Tyr Met Gly Lys Phe His Lys Ala Cys Phe Pro Asn 245 250 255 Ser Thr Asp Ala Glu Pro Val Gly Asp Phe Pro Cys Gly Lys Glu Ala 260 265 270 Pro Ala Arg Leu Cys Asp Ser Asp Thr Glu Cys Arg Glu Tyr Trp Pro 275 280 285 Gly Pro Asn Phe Gly Ile Thr Asn Phe Asp Asn Ile Leu Phe Ala Ile 290 295 300 Leu Thr Val Phe Gln Cys Ile Thr Met Glu Gly Trp Thr Asp Ile Leu 305 310 315 320 Tyr Asn Thr Asn Asp Ala Ala Gly Asn Thr Trp Asn Trp Leu Tyr Phe 325 330 335 Ile Pro Leu Ile Ile Ile Gly Ser Phe Phe Met Leu Asn Leu Val Leu 340 345 350 Gly Val Leu Ser Gly Glu Phe Ala Lys Glu Arg Glu Arg Val Glu Asn 355 360 365 Arg Arg Ala Phe Leu Lys Leu Arg Arg Gln Gln Gln Ile Glu Arg Glu 370 375 380 Leu Asn Gly Tyr Leu Glu Trp Ile Phe Lys Ala Glu Glu Val Met Leu 385 390 395 400 Ala Glu Glu Asp Lys Asn Ala Glu Glu Lys Ser Pro Leu Asp Val Leu 405 410 415 Lys Arg Ala Ala Thr Lys Lys Ser Arg Asn Asp Leu Ile His Ala Glu 420 425 430 Glu Gly Glu Asp Arg Phe Val Asp Leu Cys Ala Ala Gly Ser Pro Phe 435 440 445 Ala Arg Ala Ser Leu Lys Ser Gly Lys Thr Glu Ser Ser Ser Tyr Phe 450 455 460 Arg Arg Lys Glu Lys Met Phe Arg Phe Leu Ile Arg Arg Met Val Lys 465 470 475 480 Ala Gln Ser Phe Tyr Trp Val Val Leu Cys Val Val Ala Leu Asn Thr 485 490 495 Leu Cys Val Ala Met Val His Tyr Asn Gln Pro Gln Arg Leu Thr Thr 500 505 510 Ala Leu Tyr Phe Ala Glu Phe Val Phe Leu Gly Leu Phe Leu Thr Glu 515 520 525 Met Ser Leu Lys Met Tyr Gly Leu Gly Pro Arg Ser Tyr Phe Arg Ser 530 535 540 Ser Phe Asn Cys Phe Asp Phe Gly Val Ile Val Gly Ser Ile Phe Glu 545 550 555 560 Val Val Trp Ala Ala Ile Lys Pro Gly Thr Ser Phe Gly Ile Ser Val 565 570 575 Leu Arg Ala Leu Arg Leu Leu Arg Ile Phe Lys Val Thr Lys Tyr Trp 580 585 590 Asn Ser Leu Arg Asn Leu Val Val Ser Leu Leu Asn Ser Met Lys Ser 595 600 605 Ile Ile Ser Leu Leu Phe Leu Leu Phe Leu Phe Ile Val Val Phe Ala 610 615 620 Leu Leu Gly Met Gln Leu Phe Gly Gly Gln Phe Asn Phe Gln Asp Glu 625 630 635 640 Thr Pro Thr Thr Asn Phe Asp Thr Phe Pro Ala Ala Ile Leu Thr Val 645 650 655 Phe Gln Ile Leu Thr Gly Glu Asp Trp Asn Ala Val Met Tyr His Gly 660 665 670 Ile Glu Ser Gln Gly Gly Val Ser Lys Gly Met Phe Ser Ser Phe Tyr 675 680 685 Phe Ile Val Leu Thr Leu Phe Gly Asn Tyr Thr Leu Leu Asn Val Phe 690 695 700 Leu Ala Ile Ala Val Asp Asn Leu Ala Asn Ala Gln Glu Leu Thr Lys 705 710 715 720 Asp Glu Glu Glu Met Glu Glu Ala Ala Asn Gln Lys Leu Ala Leu Gln 725 730 735 Lys Ala Lys Glu Val Ala Glu Val Ser Pro Met Ser Ala Ala Asn Ile 740 745 750 Ser Ile Ala Ala Arg Gln Gln Asn Ser Ala Lys Ala Arg Ser Val Trp 755 760 765 Glu Gln Arg Ala Ser Gln Leu Arg Leu Gln Asn Leu Arg Ala Ser Cys 770 775 780 Glu Ala Leu Tyr Ser Glu Met Asp Pro Glu Glu Arg Leu Arg Tyr Ala 785 790 795 800 Ser Thr Arg His Val Arg Pro Asp Met Lys Thr His Met Asp Arg Pro 805 810 815 Leu Val Val Glu Pro Gly Arg Asp Gly Leu Arg Gly Pro Ala Gly Asn 820 825 830 Lys Ser Lys Pro Glu Gly Thr Glu Ala Thr Glu Gly Ala Asp Pro Pro 835 840 845 Arg Arg His His Arg His Arg Asp Arg Asp Lys Thr Ser Ala Ser Thr 850 855 860 Pro Ala Gly Gly Glu Gln Asp Arg Thr Asp Cys Pro Lys Ala Glu Ser 865 870 875 880 Thr Glu Thr Gly Ala Arg Glu Glu Arg Ala Arg Pro Arg Arg Ser His 885 890 895 Ser Lys Glu Ala Pro Gly Ala Asp Thr Gln Val Arg Cys Glu Arg Ser 900 905 910 Arg Arg His His Arg Arg Gly Ser Pro Glu Glu Ala Thr Glu Arg Glu 915 920 925 Pro Arg Arg His Arg Ala His Arg His Ala Gln Asp Ser Ser Lys Glu 930 935 940 Gly Lys Glu Gly Thr Ala Pro Val Leu Val Pro Lys Gly Glu Arg Arg 945 950 955 960 Ala Arg His Arg Gly Pro Arg Thr Gly Pro Arg Glu Thr Glu Asn Ser 965 970 975 Glu Glu Pro Thr Arg Arg His Arg Ala Lys His Lys Val Pro Pro Thr 980 985 990 Leu Glu Pro Pro Glu Arg Glu Val Ala Glu Lys Glu Ser Asn Val Val 995 1000 1005 Glu Gly Asp Lys Glu Thr Arg Asn His Gln Pro Lys Glu Pro Arg 1010 1015 1020 Cys Asp Leu Glu Ala Ile Ala Val Thr Gly Val Gly Ser Leu His 1025 1030 1035 Met Leu Pro Ser Thr Cys Leu Gln Lys Val Asp Glu Gln Pro Glu 1040 1045 1050 Asp Ala Asp Asn Gln Arg Asn Val Thr Arg Met Gly Ser Gln Pro 1055 1060 1065 Ser Asp Pro Ser Thr Thr Val His Val Pro Val Thr Leu Thr Gly 1070 1075 1080 Pro Pro Gly Glu Ala Thr Val Val Pro Ser Ala Asn Thr Asp Leu 1085 1090 1095 Glu Gly Gln Ala Glu Gly Lys Lys Glu Ala Glu Ala Asp Asp Val 1100 1105 1110 Leu Arg Arg Gly Pro Arg Pro Ile Val Pro Tyr Ser Ser Met Phe 1115 1120 1125 Cys Leu Ser Pro Thr Asn Leu Leu Arg Arg Phe Cys His Tyr Ile 1130 1135 1140 Val Thr Met Arg Tyr Phe Glu Met Val Ile Leu Val Val Ile Ala 1145 1150 1155 Leu Ser Ser Ile Ala Leu Ala Ala Glu Asp Pro Val Arg Thr Asp 1160 1165 1170 Ser Phe Arg Asn Asn Ala Leu Lys Tyr Met Asp Tyr Ile Phe Thr 1175 1180 1185 Gly Val Phe Thr Phe Glu Met Val Ile Lys Met Ile Asp Leu Gly 1190 1195 1200 Leu Leu Leu His Pro Gly Ala Tyr Phe Arg Asp Leu Trp Asn Ile 1205 1210 1215 Leu Asp Phe Ile Val Val Ser Gly Ala Leu Val Ala Phe Ala Phe 1220 1225 1230 Ser Gly Ser Lys Gly Lys Asp Ile Asn Thr Ile Lys Ser Leu Arg 1235 1240 1245 Val Leu Arg Val Leu Arg Pro Leu Lys Thr Ile Lys Arg Leu Pro 1250 1255 1260 Lys Leu Lys Ala Val Phe Asp Cys Val Val Asn Ser Leu Lys Asn 1265 1270 1275 Val Leu Asn Ile Leu Ile Val Tyr Met Leu Phe Met Phe Ile Phe 1280 1285 1290 Ala Val Ile Ala Val Gln Leu Phe Lys Gly Lys Phe Phe Tyr Cys 1295 1300 1305 Thr Asp Glu Ser Lys Glu Leu Glu Arg Asp Cys Arg Gly Gln Tyr 1310 1315 1320 Leu Asp Tyr Glu Lys Glu Glu Val Glu Ala Gln Pro Arg Gln Trp 1325 1330 1335 Lys Lys Tyr Asp Phe His Tyr Asp Asn Val Leu Trp Ala Leu Leu 1340 1345 1350 Thr Leu Phe Thr Val Ser Thr Gly Glu Gly Trp Pro Met Val Leu 1355 1360 1365 Lys His Ser Val Asp Ala Thr Tyr Glu Glu Gln Gly Pro Ser Pro 1370 1375 1380 Gly Phe Arg Met Glu Leu Ser Ile Phe Tyr Val Val Tyr Phe Val 1385 1390 1395 Val Phe Pro Phe Phe Phe Val Asn Ile Phe Val Ala Leu Ile Ile 1400 1405 1410 Ile Thr Phe Gln Glu Gln Gly Asp Lys Val Met Ser Glu Cys Ser 1415 1420 1425 Leu Glu Lys Asn Glu Arg Ala Cys Ile Asp Phe Ala Ile Ser Ala 1430 1435 1440 Lys Pro Leu Thr Arg Tyr Met Pro Gln Asn Lys Gln Ser Phe Gln 1445 1450 1455 Tyr Lys Thr Trp Thr Phe Val Val Ser Pro Pro Phe Glu Tyr Phe 1460 1465 1470 Ile Met Ala Met Ile Ala Leu Asn Thr Val Val Leu Met Met Lys 1475 1480 1485 Phe Tyr Asp Ala Pro Tyr Glu Tyr Glu Leu Met Leu Lys Cys Leu 1490 1495 1500 Asn Ile Val Phe Thr Ser Met Phe Ser Leu Glu Cys Ile Leu Lys 1505 1510 1515 Ile Ile Ala Phe Gly Val Leu Asn Tyr Phe Arg Asp Ala Trp Asn 1520 1525 1530 Val Phe Asp Phe Val Thr Val Leu Gly Ser Ile Thr Asp Ile Leu 1535 1540 1545 Val Thr Glu Ile Ala Glu Thr Asn Asn Phe Ile Asn Leu Ser Phe 1550 1555 1560 Leu Arg Leu Phe Arg Ala Ala Arg Leu Ile Lys Leu Leu Arg Gln 1565 1570 1575 Gly Tyr Thr Ile Arg Ile Leu Leu Trp Thr Phe Val Gln Ser Phe 1580 1585 1590 Lys Ala Leu Pro Tyr Val Cys Leu Leu Ile Ala Met Leu Phe Phe 1595 1600 1605 Ile Tyr Ala Ile Ile Gly Met Gln Val Phe Gly Asn Ile Ala Leu 1610 1615 1620 Asp Asp Gly Thr Ser Ile Asn Arg His Asn Asn Phe Arg Thr Phe 1625 1630 1635 Leu Gln Ala Leu Met Leu Leu Phe Arg Ser Ala Thr Gly Glu Ala 1640 1645 1650 Trp His Glu Ile Met Leu Ser Cys Leu Gly Asn Arg Ala Cys Asp 1655 1660 1665 Pro His Ala Asn Ala Ser Glu Cys Gly Ser Asp Phe Ala Tyr Phe 1670 1675 1680 Tyr Phe Val Ser Phe Ile Phe Leu Cys Ser Phe Leu Met Leu Asn 1685 1690 1695 Leu Phe Val Ala Val Ile Met Asp Asn Phe Glu Tyr Leu Thr Arg 1700 1705 1710 Asp Ser Ser Ile Leu Gly Pro His His Leu Asp Glu Phe Ile Arg 1715 1720 1725 Val Trp Ala Glu Tyr Asp Pro Ala Ala Cys Gly Arg Ile Ser Tyr 1730 1735 1740 Asn Asp Met Phe Glu Met Leu Lys His Met Ser Pro Pro Leu Gly 1745 1750 1755 Leu Gly Lys Lys Cys Pro Ala Arg Val Ala Tyr Lys Arg Leu Val 1760 1765 1770 Arg Met Asn Met Pro Ile Ser Asn Glu Asp Met Thr Val His Phe 1775 1780 1785 Thr Ser Thr Leu Met Ala Leu Ile Arg Thr Ala Leu Glu Ile Lys 1790 1795 1800 Leu Ala Pro Ala Gly Thr Lys Gln His Gln Cys Asp Ala Glu Leu 1805 1810 1815 Arg Lys Glu Ile Ser Ser Val Trp Ala Asn Leu Pro Gln Lys Thr 1820 1825 1830 Leu Asp Leu Leu Val Pro Pro His Lys Pro Asp Glu Met Thr Val 1835 1840 1845 Gly Lys Val Tyr Ala Ala Leu Met Ile Phe Asp Phe Tyr Lys Gln 1850 1855 1860 Asn Lys Thr Thr Arg Asp Gln Thr His Gln Ala Pro Gly Gly Leu 1865 1870 1875 Ser Gln Met Gly Pro Val Ser Leu Phe His Pro Leu Lys Ala Thr 1880 1885 1890 Leu Glu Gln Thr Gln Pro Ala Val Leu Arg Gly Ala Arg Val Phe 1895 1900 1905 Leu Arg Gln Lys Ser Ala Thr Ser Leu Ser Asn Gly Gly Ala Ile 1910 1915 1920 Gln Thr Gln Glu Ser Gly Ile Lys Glu Ser Leu Ser Trp Gly Thr 1925 1930 1935 Gln Arg Thr Gln Asp Val Leu Tyr Glu Ala Arg Ala Pro Leu Glu 1940 1945 1950 Arg Gly His Ser Ala Glu Ile Pro Val Gly Gln Pro Gly Ala Leu 1955 1960 1965 Ala Val Asp Val Gln Met Gln Asn Met Thr Leu Arg Gly Pro Asp 1970 1975 1980 Gly Glu Pro Gln Pro Gly Leu Glu Ser Gln Gly Arg Ala Ala Ser 1985 1990 1995 Met Pro Arg Leu Ala Ala Glu Thr Gln Pro Ala Pro Asn Ala Ser 2000 2005 2010 Pro Met Lys Arg Ser Ile Ser Thr Leu Ala Pro Arg Pro His Gly 2015 2020 2025 Thr Gln Leu Cys Asn Thr Val Leu Asp Arg Pro Pro Pro Ser Gln 2030 2035 2040 Val Ser His His His His His Arg Cys His Arg Arg Arg Asp Lys 2045 2050 2055 Lys Gln Arg Ser Leu Glu Lys Gly Pro Ser Leu Ser Val Asp Thr 2060 2065 2070 Glu Gly Ala Pro Ser Thr Ala Ala Gly Ser Gly Leu Pro His Gly 2075 2080 2085 Glu Gly Ser Thr Gly Cys Arg Arg Glu Arg Lys Gln Glu Arg Gly 2090 2095 2100 Arg Ser Gln Glu Arg Arg Gln Pro Ser Ser Ser Ser Ser Glu Lys 2105 2110 2115 Gln Arg Phe Tyr Ser Cys Asp Arg Phe Gly Ser Arg Glu Pro Pro 2120 2125 2130 Gln Pro Lys Pro Ser Leu Ser Ser His Pro Ile Ser Pro Thr Ala 2135 2140 2145 Ala Leu Glu Pro Gly Pro His Pro Gln Gly Ser Gly Ser Val Asn 2150 2155 2160 Gly Ser Pro Leu Met Ser Thr Ser Gly Ala Ser Thr Pro Gly Arg 2165 2170 2175 Gly Gly Arg Arg Gln Leu Pro Gln Thr Pro Leu Thr Pro Arg Pro 2180 2185 2190 Ser Ile Thr Tyr Lys Thr Ala Asn Ser Ser Pro Val His Phe Ala 2195 2200 2205 Glu Gly Gln Ser Gly Leu Pro Ala Phe Ser Pro Gly Arg Leu Ser 2210 2215 2220 Arg Gly Leu Ser Glu His Asn Ala Leu Leu Gln Lys Glu Pro Leu 2225 2230 2235 Ser Gln Pro Leu Ala Ser Gly Ser Arg Ile Gly Ser Asp Pro Tyr 2240 2245 2250 Leu Gly Gln Arg Leu Asp Ser Glu Ala Ser Ala His Asn Leu Pro 2255 2260 2265 Glu Asp Thr Leu Thr Phe Glu Glu Ala Val Ala Thr Asn Ser Gly 2270 2275 2280 Arg Ser Ser Arg Thr Ser Tyr Val Ser Ser Leu Thr Ser Gln Ser 2285 2290 2295 His Pro Leu Arg Arg Val Pro Asn Gly Tyr His Cys Thr Leu Gly 2300 2305 2310 Leu Ser Thr Gly Val Arg Ala Arg His Ser Tyr His His Pro Asp 2315 2320 2325 Gln Asp His Trp Cys 2330 29 7011 DNA Rattus norvegicus CDS (1)..(7011) 29 atg gtc cgc ttc ggg gac gag cta ggc ggc cgc tat ggg ggc acc ggc 48 Met Val Arg Phe Gly Asp Glu Leu Gly Gly Arg Tyr Gly Gly Thr Gly 1 5 10 15 ggc ggg gag cgg gct cgg ggc ggc ggg gcc ggc ggg gcc ggt ggc ccg 96 Gly Gly Glu Arg Ala Arg Gly Gly Gly Ala Gly Gly Ala Gly Gly Pro 20 25 30 ggc cag ggg ggt ctg ccg ccg ggc cag cgg gtc ctg tac aag cag tcc 144 Gly Gln Gly Gly Leu Pro Pro Gly Gln Arg Val Leu Tyr Lys Gln Ser 35 40 45 att gcg caa cgc gca cgg acc atg gcc ctg tac aac ccc atc cca gtc 192 Ile Ala Gln Arg Ala Arg Thr Met Ala Leu Tyr Asn Pro Ile Pro Val 50 55 60 aag cag aac tgc ttc acc gtc aac cgc tcg ctc ttc gtc ttc agc gag 240 Lys Gln Asn Cys Phe Thr Val Asn Arg Ser Leu Phe Val Phe Ser Glu 65 70 75 80 gac aac gtc gtc cgc aaa tat gct aag cgc atc acc gaa tgg ccg ccc 288 Asp Asn Val Val Arg Lys Tyr Ala Lys Arg Ile Thr Glu Trp Pro Pro 85 90 95 ttc gaa tat atg atc ctg gcc acc atc atc gcc aac tgt att gtc ctg 336 Phe Glu Tyr Met Ile Leu Ala Thr Ile Ile Ala Asn Cys Ile Val Leu 100 105 110 gcc ctg gag cag cac ctc cct gat ggg gac aag act ccc atg tct gaa 384 Ala Leu Glu Gln His Leu Pro Asp Gly Asp Lys Thr Pro Met Ser Glu 115 120 125 cga ctg gat gac acg gaa cct tac ttc atc ggc atc ttt tgc ttc gag 432 Arg Leu Asp Asp Thr Glu Pro Tyr Phe Ile Gly Ile Phe Cys Phe Glu 130 135 140 gcg ggc atc aag atc ata gct ctg ggc ttc gtg ttc cac aaa ggc tcc 480 Ala Gly Ile Lys Ile Ile Ala Leu Gly Phe Val Phe His Lys Gly Ser 145 150 155 160 tac ctc cgg aat ggc tgg aac gtc atg gac ttc gtg gtg gtc ctc aca 528 Tyr Leu Arg Asn Gly Trp Asn Val Met Asp Phe Val Val Val Leu Thr 165 170 175 gag att ctt gcc aca gct gga act gac ttt gat ctg cgc acc ctg agg 576 Glu Ile Leu Ala Thr Ala Gly Thr Asp Phe Asp Leu Arg Thr Leu Arg 180 185 190 gct gtg cgt gtg ctt agg ccc ctg aag ttg gtg tct gga att cca agc 624 Ala Val Arg Val Leu Arg Pro Leu Lys Leu Val Ser Gly Ile Pro Ser 195 200 205 ttg cag gtg gtg ctc aag tcc atc atg aag gcc atg gtc ccg ctg ctg 672 Leu Gln Val Val Leu Lys Ser Ile Met Lys Ala Met Val Pro Leu Leu 210 215 220 cag atc ggg ctg ctg ctc ttc ttc gcc atc ctc atg ttc gct atc atc 720 Gln Ile Gly Leu Leu Leu Phe Phe Ala Ile Leu Met Phe Ala Ile Ile 225 230 235 240 ggc ctc gag ttc tat atg ggc aaa ttc cat aag gcc tgc ttc ccc aac 768 Gly Leu Glu Phe Tyr Met Gly Lys Phe His Lys Ala Cys Phe Pro Asn 245 250 255 agc aca gat gca gag cct gtg ggt gac ttt cct tgt ggc aag gag gcc 816 Ser Thr Asp Ala Glu Pro Val Gly Asp Phe Pro Cys Gly Lys Glu Ala 260 265 270 cct gct cgt ctg tgt gac agt gac acc gaa tgc cgg gag tac tgg cca 864 Pro Ala Arg Leu Cys Asp Ser Asp Thr Glu Cys Arg Glu Tyr Trp Pro 275 280 285 gga ccc aac ttt ggc atc acc aat ttt gac aac atc ctg ttt gcc atc 912 Gly Pro Asn Phe Gly Ile Thr Asn Phe Asp Asn Ile Leu Phe Ala Ile 290 295 300 ttg acc gtg ttc cag tgt atc acc atg gag ggc tgg act gac atc ctc 960 Leu Thr Val Phe Gln Cys Ile Thr Met Glu Gly Trp Thr Asp Ile Leu 305 310 315 320 tac aat aca aat gat gcg gcc ggc aac acg tgg aac tgg ttg tac ttc 1008 Tyr Asn Thr Asn Asp Ala Ala Gly Asn Thr Trp Asn Trp Leu Tyr Phe 325 330 335 atc ccc ctc atc atc att ggc tcc ttc ttc atg ctc aac ctg gtg ctc 1056 Ile Pro Leu Ile Ile Ile Gly Ser Phe Phe Met Leu Asn Leu Val Leu 340 345 350 ggt gtg ctt tca gga gag ttt gcc aaa gag cgg gag cga gtc gag aac 1104 Gly Val Leu Ser Gly Glu Phe Ala Lys Glu Arg Glu Arg Val Glu Asn 355 360 365 cgc cgt gcc ttc ctg aag ctc cgc agg cag cag cag att gag cga gaa 1152 Arg Arg Ala Phe Leu Lys Leu Arg Arg Gln Gln Gln Ile Glu Arg Glu 370 375 380 ctg aat ggg tac ttg gag tgg atc ttc aag gcg gag gaa gtc atg ttg 1200 Leu Asn Gly Tyr Leu Glu Trp Ile Phe Lys Ala Glu Glu Val Met Leu 385 390 395 400 gca gag gag gac aag aac gca gaa gag aag tcc cct ttg gat gca gtg 1248 Ala Glu Glu Asp Lys Asn Ala Glu Glu Lys Ser Pro Leu Asp Ala Val 405 410 415 ttg aag aga gct gct acc aag aag agc cga aat gac ctc atc cat gca 1296 Leu Lys Arg Ala Ala Thr Lys Lys Ser Arg Asn Asp Leu Ile His Ala 420 425 430 gaa gag ggg gag gac cgg ttt gta gac ctc tgt gct gct ggg tct ccc 1344 Glu Glu Gly Glu Asp Arg Phe Val Asp Leu Cys Ala Ala Gly Ser Pro 435 440 445 ttt gct cgt gcc agc ctc aag agt ggg aag aca gag agc tca tcg tac 1392 Phe Ala Arg Ala Ser Leu Lys Ser Gly Lys Thr Glu Ser Ser Ser Tyr 450 455 460 ttc cgg agg aag gag aag atg ttc cgg ttc ctt atc cgt cgt atg gtg 1440 Phe Arg Arg Lys Glu Lys Met Phe Arg Phe Leu Ile Arg Arg Met Val 465 470 475 480 aaa gca cag agc ttc tac tgg gtg gta ctg tgc gtg gtg gcc ctg aac 1488 Lys Ala Gln Ser Phe Tyr Trp Val Val Leu Cys Val Val Ala Leu Asn 485 490 495 acg ttg tgt gtg gcc atg gta cac tat aat cag cct cag cgg ctt acc 1536 Thr Leu Cys Val Ala Met Val His Tyr Asn Gln Pro Gln Arg Leu Thr 500 505 510 act gca ctg tac ttt gca gag ttt gtt ttc ctg ggt ctc ttc ctc aca 1584 Thr Ala Leu Tyr Phe Ala Glu Phe Val Phe Leu Gly Leu Phe Leu Thr 515 520 525 gag atg tcc ctg aag atg tac ggt cta ggg ccc aga agc tac ttc cgg 1632 Glu Met Ser Leu Lys Met Tyr Gly Leu Gly Pro Arg Ser Tyr Phe Arg 530 535 540 tct tcc ttc aac tgc ttt gac ttt ggg gtg att gtg ggg agt atc ttt 1680 Ser Ser Phe Asn Cys Phe Asp Phe Gly Val Ile Val Gly Ser Ile Phe 545 550 555 560 gaa gta gtc tgg gct gcc atc aag cca gga acc tcc ttc gga atc agt 1728 Glu Val Val Trp Ala Ala Ile Lys Pro Gly Thr Ser Phe Gly Ile Ser 565 570 575 gtg ctg cgg gct ctc cga ctg ctg agg att ttc aaa gtc acc aag tat 1776 Val Leu Arg Ala Leu Arg Leu Leu Arg Ile Phe Lys Val Thr Lys Tyr 580 585 590 tgg aac tcc ctg agg aac ctg gtt gtt tcc ctc ctc aac tcc atg aag 1824 Trp Asn Ser Leu Arg Asn Leu Val Val Ser Leu Leu Asn Ser Met Lys 595 600 605 tcc atc atc agc ctt ctc ttc ctg ctt ttc ctt ttc att gtg gtc ttc 1872 Ser Ile Ile Ser Leu Leu Phe Leu Leu Phe Leu Phe Ile Val Val Phe 610 615 620 gct ctg ttg ggg atg cag ctg ttt ggg gga cag ttc aac ttt caa gat 1920 Ala Leu Leu Gly Met Gln Leu Phe Gly Gly Gln Phe Asn Phe Gln Asp 625 630 635 640 gag act cca acc acc aat ttt gat acc ttc cca gct gcc atc ctc act 1968 Glu Thr Pro Thr Thr Asn Phe Asp Thr Phe Pro Ala Ala Ile Leu Thr 645 650 655 gtg ttt cag att ctg aca gga gag gac tgg aat gca gtc atg tat cat 2016 Val Phe Gln Ile Leu Thr Gly Glu Asp Trp Asn Ala Val Met Tyr His 660 665 670 ggg att gag tca caa gga gga gtc agc aaa ggc atg ttt tca tcc ttt 2064 Gly Ile Glu Ser Gln Gly Gly Val Ser Lys Gly Met Phe Ser Ser Phe 675 680 685 tac ttc atc gtc ctg aca ctg ttt gga aac tac acc ctg ttg aac gtt 2112 Tyr Phe Ile Val Leu Thr Leu Phe Gly Asn Tyr Thr Leu Leu Asn Val 690 695 700 ttc ttg gcc att gct gtg gac aac ctt gcc aat gcc cag gag ttg acc 2160 Phe Leu Ala Ile Ala Val Asp Asn Leu Ala Asn Ala Gln Glu Leu Thr 705 710 715 720 aag gat gaa gag gag atg gaa gag gca gcc aat cag aag ctt gct ctt 2208 Lys Asp Glu Glu Glu Met Glu Glu Ala Ala Asn Gln Lys Leu Ala Leu 725 730 735 cag aag gcc aaa gaa gta gct gaa gtc agc ccc atg tct gct gcc aac 2256 Gln Lys Ala Lys Glu Val Ala Glu Val Ser Pro Met Ser Ala Ala Asn 740 745 750 atc tcc att gct gcc agg cag cag aac tcg gcc aag gcg cgc tca gta 2304 Ile Ser Ile Ala Ala Arg Gln Gln Asn Ser Ala Lys Ala Arg Ser Val 755 760 765 tgg gag cag cgg gcc agt cag cta agg ctc cag aac ctg cgt gcc agc 2352 Trp Glu Gln Arg Ala Ser Gln Leu Arg Leu Gln Asn Leu Arg Ala Ser 770 775 780 tgt gag gca ctg tac agt gag atg gac ccg gag gag cgc ctg cgt tat 2400 Cys Glu Ala Leu Tyr Ser Glu Met Asp Pro Glu Glu Arg Leu Arg Tyr 785 790 795 800 gcc agc acg cgc cac gtg agg cca gac atg aag aca cac atg gac cga 2448 Ala Ser Thr Arg His Val Arg Pro Asp Met Lys Thr His Met Asp Arg 805 810 815 ccc cta gtg gtg gaa cct ggt cgg gat ggc ctg cgg gga ccc gcc ggg 2496 Pro Leu Val Val Glu Pro Gly Arg Asp Gly Leu Arg Gly Pro Ala Gly 820 825 830 aac aag tca aag cct gag ggc acg gag gcc acc gaa ggt gcg gat cca 2544 Asn Lys Ser Lys Pro Glu Gly Thr Glu Ala Thr Glu Gly Ala Asp Pro 835 840 845 cca cgc cga cac cac cgg cat cgt gat agg gac aag acc tca gcc tca 2592 Pro Arg Arg His His Arg His Arg Asp Arg Asp Lys Thr Ser Ala Ser 850 855 860 acc cct gct gga ggc gaa cag gac agg aca gac tgc cca aag gcc gaa 2640 Thr Pro Ala Gly Gly Glu Gln Asp Arg Thr Asp Cys Pro Lys Ala Glu 865 870 875 880 agc acc gag acc ggg gcc cgg gag gaa cgt gcg cgc cct cgt cga agt 2688 Ser Thr Glu Thr Gly Ala Arg Glu Glu Arg Ala Arg Pro Arg Arg Ser 885 890 895 cac agc aag gag gct cca ggg gct gac aca caa gtg cgt tgt gag cgc 2736 His Ser Lys Glu Ala Pro Gly Ala Asp Thr Gln Val Arg Cys Glu Arg 900 905 910 agt aga cgt cac cac cgg cgc gga tcc ccg gag gag gcc act gaa cgg 2784 Ser Arg Arg His His Arg Arg Gly Ser Pro Glu Glu Ala Thr Glu Arg 915 920 925 gaa cct cgg cgc cac cgt gcc cac cgg cac gca cag gac tca agc aag 2832 Glu Pro Arg Arg His Arg Ala His Arg His Ala Gln Asp Ser Ser Lys 930 935 940 gaa ggc aag gag ggc act gca ccg gtg ctt gta ccc aag ggc gag cgt 2880 Glu Gly Lys Glu Gly Thr Ala Pro Val Leu Val Pro Lys Gly Glu Arg 945 950 955 960 cgc gca aga cat cga ggc ccg cgt acg ggc ccc cgt gag aca gag aac 2928 Arg Ala Arg His Arg Gly Pro Arg Thr Gly Pro Arg Glu Thr Glu Asn 965 970 975 agt gag gag ccc aca cgc agg cac cgt gca aag cat aag gtg cca cca 2976 Ser Glu Glu Pro Thr Arg Arg His Arg Ala Lys His Lys Val Pro Pro 980 985 990 aca ctt gag ccc cca gag agg gag gtt gca gag aag gag agc aac gtg 3024 Thr Leu Glu Pro Pro Glu Arg Glu Val Ala Glu Lys Glu Ser Asn Val 995 1000 1005 gtg gaa ggg gat aag gaa act cga aat cac cag ccc aag gaa cct 3069 Val Glu Gly Asp Lys Glu Thr Arg Asn His Gln Pro Lys Glu Pro 1010 1015 1020 cgc tgt gac ctg gag gcc att gcg gtt aca ggc gtg ggc tct ctg 3114 Arg Cys Asp Leu Glu Ala Ile Ala Val Thr Gly Val Gly Ser Leu 1025 1030 1035 cac atg ctg ccc agc acc tgt ctc cag aaa gtg gac gaa cag cca 3159 His Met Leu Pro Ser Thr Cys Leu Gln Lys Val Asp Glu Gln Pro 1040 1045 1050 gag gat gca gac aac cag cgt aat gtc acc cgg atg ggc agt cag 3204 Glu Asp Ala Asp Asn Gln Arg Asn Val Thr Arg Met Gly Ser Gln 1055 1060 1065 ccc tca gac ccc agc acc act gtg cat gtc cca gtg aca ctg aca 3249 Pro Ser Asp Pro Ser Thr Thr Val His Val Pro Val Thr Leu Thr 1070 1075 1080 ggc cct ccc ggg gag gcc act gta gtt ccc agt gct aac acg gac 3294 Gly Pro Pro Gly Glu Ala Thr Val Val Pro Ser Ala Asn Thr Asp 1085 1090 1095 ctg gaa ggc caa gcg gag ggc aag aag gag gca gag gct gac gat 3339 Leu Glu Gly Gln Ala Glu Gly Lys Lys Glu Ala Glu Ala Asp Asp 1100 1105 1110 gtg ctg aga aga ggc ccc agg ccc atc gtt ccc tac agt tcc atg 3384 Val Leu Arg Arg Gly Pro Arg Pro Ile Val Pro Tyr Ser Ser Met 1115 1120 1125 ttc tgc ctc agc ccc acc aac cta ctc cgt cgc ttc tgc cat tac 3429 Phe Cys Leu Ser Pro Thr Asn Leu Leu Arg Arg Phe Cys His Tyr 1130 1135 1140 att gtg acc atg cgg tac ttt gag atg gtg att ctt gtg gtc atc 3474 Ile Val Thr Met Arg Tyr Phe Glu Met Val Ile Leu Val Val Ile 1145 1150 1155 gcc ttg agc agc att gcc ctg gct gct gag gat ccc gtg cgg acc 3519 Ala Leu Ser Ser Ile Ala Leu Ala Ala Glu Asp Pro Val Arg Thr 1160 1165 1170 gac tca ttc cgg aac aat gct ctg aag tac atg gac tac atc ttt 3564 Asp Ser Phe Arg Asn Asn Ala Leu Lys Tyr Met Asp Tyr Ile Phe 1175 1180 1185 aca gga gtc ttc acc ttt gag atg gtc ata aag atg ata gac ttg 3609 Thr Gly Val Phe Thr Phe Glu Met Val Ile Lys Met Ile Asp Leu 1190 1195 1200 ggc ctg ctg ctg cac cct ggg gcc tac ttc cgg gac ctg tgg aac 3654 Gly Leu Leu Leu His Pro Gly Ala Tyr Phe Arg Asp Leu Trp Asn 1205 1210 1215 att ctg gac ttc att gtt gtc agt gga gcc ctg gtg gca ttt gca 3699 Ile Leu Asp Phe Ile Val Val Ser Gly Ala Leu Val Ala Phe Ala 1220 1225 1230 ttc tcg agc ttc atg gga gga tcc aaa ggg aaa gac atc aat acc 3744 Phe Ser Ser Phe Met Gly Gly Ser Lys Gly Lys Asp Ile Asn Thr 1235 1240 1245 atc aag tct ctg aga gtc ctg cga gtc ctg cgg ccc ctc aag acc 3789 Ile Lys Ser Leu Arg Val Leu Arg Val Leu Arg Pro Leu Lys Thr 1250 1255 1260 atc aag cgg ctg cct aaa ctc aag gct gtg ttt gac tgt gtg gtg 3834 Ile Lys Arg Leu Pro Lys Leu Lys Ala Val Phe Asp Cys Val Val 1265 1270 1275 aac tct ctg aag aat gtc ttg aac atc ctg atc gtc tac atg ctc 3879 Asn Ser Leu Lys Asn Val Leu Asn Ile Leu Ile Val Tyr Met Leu 1280 1285 1290 ttc atg ttt ata ttt gcc gtc atc gcc gtc caa ctc ttc aaa ggg 3924 Phe Met Phe Ile Phe Ala Val Ile Ala Val Gln Leu Phe Lys Gly 1295 1300 1305 aag ttc ttt tac tgc act gat gag tcc aag gag ctg gag cgg gac 3969 Lys Phe Phe Tyr Cys Thr Asp Glu Ser Lys Glu Leu Glu Arg Asp 1310 1315 1320 tgc agg ggt cag tat ttg gat tat gag aag gaa gag gta gaa gcc 4014 Cys Arg Gly Gln Tyr Leu Asp Tyr Glu Lys Glu Glu Val Glu Ala 1325 1330 1335 cag cca agg cag tgg aag aaa tat gac ttc cac tat gac aat gtg 4059 Gln Pro Arg Gln Trp Lys Lys Tyr Asp Phe His Tyr Asp Asn Val 1340 1345 1350 ctc tgg gcc ttg ctg act ctg ttt acg gtg tcc aca gga gag ggg 4104 Leu Trp Ala Leu Leu Thr Leu Phe Thr Val Ser Thr Gly Glu Gly 1355 1360 1365 tgg ccc atg gtg ctg aaa cac tct gtg gac gcc acc tat gag gag 4149 Trp Pro Met Val Leu Lys His Ser Val Asp Ala Thr Tyr Glu Glu 1370 1375 1380 cag ggg cca agc ccc ggg ttt cgg atg gag ctt tcc atc ttc tat 4194 Gln Gly Pro Ser Pro Gly Phe Arg Met Glu Leu Ser Ile Phe Tyr 1385 1390 1395 gtg gtc tac ttt gtg gtc ttc cct ttt ttc ttt gtc aac atc ttt 4239 Val Val Tyr Phe Val Val Phe Pro Phe Phe Phe Val Asn Ile Phe 1400 1405 1410 gtg gcc ttg atc atc atc acc ttc cag gag cag ggg gac aag gtg 4284 Val Ala Leu Ile Ile Ile Thr Phe Gln Glu Gln Gly Asp Lys Val 1415 1420 1425 atg tct gag tgc agt ctg gaa aag aat gag agg gct tgc att gac 4329 Met Ser Glu Cys Ser Leu Glu Lys Asn Glu Arg Ala Cys Ile Asp 1430 1435 1440 ttt gcc atc agc gcc aaa ccc ctg aca cgg tac atg cct cag aac 4374 Phe Ala Ile Ser Ala Lys Pro Leu Thr Arg Tyr Met Pro Gln Asn 1445 1450 1455 aag cag tcg ttc cag tat aag aca tgg aca ttt gtg gtc tct cca 4419 Lys Gln Ser Phe Gln Tyr Lys Thr Trp Thr Phe Val Val Ser Pro 1460 1465 1470 ccc ttt gag tac ttc att atg gcc atg ata gcc ctc aac aca gtg 4464 Pro Phe Glu Tyr Phe Ile Met Ala Met Ile Ala Leu Asn Thr Val 1475 1480 1485 gtg ctg atg atg aag ttc tac gat gcc cct tat gag tac gag ctg 4509 Val Leu Met Met Lys Phe Tyr Asp Ala Pro Tyr Glu Tyr Glu Leu 1490 1495 1500 atg ctg aag tgc ttg aac atc gtc ttc aca tcc atg ttc tct ctg 4554 Met Leu Lys Cys Leu Asn Ile Val Phe Thr Ser Met Phe Ser Leu 1505 1510 1515 gag tgc atc ctg aag atc atc gcc ttc ggg gtg ttg aac tac ttc 4599 Glu Cys Ile Leu Lys Ile Ile Ala Phe Gly Val Leu Asn Tyr Phe 1520 1525 1530 aga gat gcc tgg aac gtc ttt gac ttt gtc act gtt ttg gga agt 4644 Arg Asp Ala Trp Asn Val Phe Asp Phe Val Thr Val Leu Gly Ser 1535 1540 1545 att act gat att tta gta acg gag att gcg aac aac ttc atc aac 4689 Ile Thr Asp Ile Leu Val Thr Glu Ile Ala Asn Asn Phe Ile Asn 1550 1555 1560 ttg agc ttc ctt cgc ctc ttc cgg gca gca cgg ctg atc aag ctc 4734 Leu Ser Phe Leu Arg Leu Phe Arg Ala Ala Arg Leu Ile Lys Leu 1565 1570 1575 tgt cgc cag ggc tac acc atc cgc atc ttg tta tgg acc ttt gtc 4779 Cys Arg Gln Gly Tyr Thr Ile Arg Ile Leu Leu Trp Thr Phe Val 1580 1585 1590 cag tcc ttt aag gcg ctg ccc tac gtg tgc ctc ctc att gcc atg 4824 Gln Ser Phe Lys Ala Leu Pro Tyr Val Cys Leu Leu Ile Ala Met 1595 1600 1605 ctg ttc ttc atc tac gcc atc atc ggc atg cag gtt ttt gga aac 4869 Leu Phe Phe Ile Tyr Ala Ile Ile Gly Met Gln Val Phe Gly Asn 1610 1615 1620 att gcc ctt gat gat ggc acc agc atc aac cga cac aac aac ttc 4914 Ile Ala Leu Asp Asp Gly Thr Ser Ile Asn Arg His Asn Asn Phe 1625 1630 1635 cgg aca ttt ctg caa gcc tta atg ctg ttg ttc agg agt gcc act 4959 Arg Thr Phe Leu Gln Ala Leu Met Leu Leu Phe Arg Ser Ala Thr 1640 1645 1650 ggg gag gcc tgg cac gaa atc atg ctg tct tgc ctg ggc aac cgg 5004 Gly Glu Ala Trp His Glu Ile Met Leu Ser Cys Leu Gly Asn Arg 1655 1660 1665 gcc tgc gac cca cat gcc aac gcc agc gaa tgc ggg agc gac ttt 5049 Ala Cys Asp Pro His Ala Asn Ala Ser Glu Cys Gly Ser Asp Phe 1670 1675 1680 gcc tat ttt tat ttt gtc tcc ttc atc ttc ctc tgt tcc ttt ctg 5094 Ala Tyr Phe Tyr Phe Val Ser Phe Ile Phe Leu Cys Ser Phe Leu 1685 1690 1695 atg ctg aac ctc ttt gtt gct gtg atc atg gac aat ttc gaa tac 5139 Met Leu Asn Leu Phe Val Ala Val Ile Met Asp Asn Phe Glu Tyr 1700 1705 1710 ctc acg cgg gat tct tcc atc cta ggg ccg cac cac ctc gat gaa 5184 Leu Thr Arg Asp Ser Ser Ile Leu Gly Pro His His Leu Asp Glu 1715 1720 1725 ttc att cgc gtc tgg gct gaa tac gac cca gct gcg tgt ggg cgc 5229 Phe Ile Arg Val Trp Ala Glu Tyr Asp Pro Ala Ala Cys Gly Arg 1730 1735 1740 atc agt tac aat gac atg ttt gag atg ctg aaa cac atg tcc cca 5274 Ile Ser Tyr Asn Asp Met Phe Glu Met Leu Lys His Met Ser Pro 1745 1750 1755 cct ctg ggt ttg ggg aag aaa tgc ccg gct cga gtt gca tac aag 5319 Pro Leu Gly Leu Gly Lys Lys Cys Pro Ala Arg Val Ala Tyr Lys 1760 1765 1770 cgc ctg gtt cga atg aac atg ccc ata tcc aat gag gac atg acg 5364 Arg Leu Val Arg Met Asn Met Pro Ile Ser Asn Glu Asp Met Thr 1775 1780 1785 gta cac ttt aca tcc aca ctg atg gcc ctc atc cgg acg gca ctg 5409 Val His Phe Thr Ser Thr Leu Met Ala Leu Ile Arg Thr Ala Leu 1790 1795 1800 gag atc aag ctt gcc cca gcg ggg aca aaa cag cac caa tgt gat 5454 Glu Ile Lys Leu Ala Pro Ala Gly Thr Lys Gln His Gln Cys Asp 1805 1810 1815 gct gag ctg agg aag gag atc tct tct gtg tgg gct aat ctg ccc 5499 Ala Glu Leu Arg Lys Glu Ile Ser Ser Val Trp Ala Asn Leu Pro 1820 1825 1830 cag aag act ctg gac tta ctg gtg cca ccc cac aaa cct gac gag 5544 Gln Lys Thr Leu Asp Leu Leu Val Pro Pro His Lys Pro Asp Glu 1835 1840 1845 atg aca gtg ggg aag gtc tat gcg gct ctc atg ata ttt gac ttc 5589 Met Thr Val Gly Lys Val Tyr Ala Ala Leu Met Ile Phe Asp Phe 1850 1855 1860 tac aaa cag aac aaa acc acc aga gat cag act cac caa gct cct 5634 Tyr Lys Gln Asn Lys Thr Thr Arg Asp Gln Thr His Gln Ala Pro 1865 1870 1875 gga ggc ctg tcc cag atg ggt cct gtt tcc cta ttc cat cct ctg 5679 Gly Gly Leu Ser Gln Met Gly Pro Val Ser Leu Phe His Pro Leu 1880 1885 1890 aag gcc acc ctg gag cag aca cag ccc gct gtg ctc cga gga gct 5724 Lys Ala Thr Leu Glu Gln Thr Gln Pro Ala Val Leu Arg Gly Ala 1895 1900 1905 cgg gtt ttc ctt cga caa aag agt gca act tcc ctc agc aat ggg 5769 Arg Val Phe Leu Arg Gln Lys Ser Ala Thr Ser Leu Ser Asn Gly 1910 1915 1920 ggc gcc ata caa acc cag gaa agt ggc atc aag gag tcc ctg tcc 5814 Gly Ala Ile Gln Thr Gln Glu Ser Gly Ile Lys Glu Ser Leu Ser 1925 1930 1935 tgg ggc acg cag agg acc cag gac gta ctt tat gag gcc aga gca 5859 Trp Gly Thr Gln Arg Thr Gln Asp Val Leu Tyr Glu Ala Arg Ala 1940 1945 1950 cct cta gaa cgt ggc cat tct gca gag atc cct gtg ggg cag cca 5904 Pro Leu Glu Arg Gly His Ser Ala Glu Ile Pro Val Gly Gln Pro 1955 1960 1965 gga gca ctg gct gta gat gtc cag atg cag aac atg aca ttg aga 5949 Gly Ala Leu Ala Val Asp Val Gln Met Gln Asn Met Thr Leu Arg 1970 1975 1980 gga ccg gat ggg gag ccc cag cct ggc ctg gag agc caa ggc cga 5994 Gly Pro Asp Gly Glu Pro Gln Pro Gly Leu Glu Ser Gln Gly Arg 1985 1990 1995 gcg gcc tct atg cca cgc ctg gcg gca gaa aca cag ccg gcc cct 6039 Ala Ala Ser Met Pro Arg Leu Ala Ala Glu Thr Gln Pro Ala Pro 2000 2005 2010 aat gcc agc ccc atg aag cgc tcc atc tcc aca ctg gct cca cgc 6084 Asn Ala Ser Pro Met Lys Arg Ser Ile Ser Thr Leu Ala Pro Arg 2015 2020 2025 ccg cat ggg act cag ctt tgc aac aca gtc ctg gac cgg cca cct 6129 Pro His Gly Thr Gln Leu Cys Asn Thr Val Leu Asp Arg Pro Pro 2030 2035 2040 cct agc cag gtg tcc cat cac cac cac cac cgc tgc cac cgg cgc 6174 Pro Ser Gln Val Ser His His His His His Arg Cys His Arg Arg 2045 2050 2055 agg gac aag aag cag agg tcc ctg gaa aag ggg ccc agc ctg tct 6219 Arg Asp Lys Lys Gln Arg Ser Leu Glu Lys Gly Pro Ser Leu Ser 2060 2065 2070 gtt gac aca gaa ggt gca cca agt act gct gca gga tct ggc ctg 6264 Val Asp Thr Glu Gly Ala Pro Ser Thr Ala Ala Gly Ser Gly Leu 2075 2080 2085 ccc cat gga gaa ggg tcc aca ggc tgc cgg cgg gag cgt aag caa 6309 Pro His Gly Glu Gly Ser Thr Gly Cys Arg Arg Glu Arg Lys Gln 2090 2095 2100 gag cga ggc cgg tcc cag gag cgg agg cag ccc tcc tcc tct tct 6354 Glu Arg Gly Arg Ser Gln Glu Arg Arg Gln Pro Ser Ser Ser Ser 2105 2110 2115 tca gag aag cag cgc ttc tat tcc tgt gac cgc ttt ggg agc cgg 6399 Ser Glu Lys Gln Arg Phe Tyr Ser Cys Asp Arg Phe Gly Ser Arg 2120 2125 2130 gag ccc cca caa cct aag ccc tcc ctc agt agc cac ccc ata tcg 6444 Glu Pro Pro Gln Pro Lys Pro Ser Leu Ser Ser His Pro Ile Ser 2135 2140 2145 cca aca gcg gca cta gag cca gga ccc cac ccg cag ggc agt ggt 6489 Pro Thr Ala Ala Leu Glu Pro Gly Pro His Pro Gln Gly Ser Gly 2150 2155 2160 tcc gtt aat ggg agc ccc ttg atg tca aca tct ggt gct agc acg 6534 Ser Val Asn Gly Ser Pro Leu Met Ser Thr Ser Gly Ala Ser Thr 2165 2170 2175 ccg ggc cga ggt ggg cgg agg cag ctc ccc cag act ccc ctg acc 6579 Pro Gly Arg Gly Gly Arg Arg Gln Leu Pro Gln Thr Pro Leu Thr 2180 2185 2190 cca cgc ccc agc atc acc tac aag acg gcc aat tcc tcg cct gtc 6624 Pro Arg Pro Ser Ile Thr Tyr Lys Thr Ala Asn Ser Ser Pro Val 2195 2200 2205 cac ttt gct gag ggt cag agt ggc ctt cca gcc ttc tcc cct ggc 6669 His Phe Ala Glu Gly Gln Ser Gly Leu Pro Ala Phe Ser Pro Gly 2210 2215 2220 cgt ctc agc cgc ggc ctt tct gaa cac aat gcc ctg ctc cag aaa 6714 Arg Leu Ser Arg Gly Leu Ser Glu His Asn Ala Leu Leu Gln Lys 2225 2230 2235 gag ccc ctg agc cag cct cta gct tct ggc tcc cgc att ggc tct 6759 Glu Pro Leu Ser Gln Pro Leu Ala Ser Gly Ser Arg Ile Gly Ser 2240 2245 2250 gac cct tac cta ggg cag cgt ctg gac agt gag gcc tct gcc cac 6804 Asp Pro Tyr Leu Gly Gln Arg Leu Asp Ser Glu Ala Ser Ala His 2255 2260 2265 aac ctg cct gag gat aca ctc acc ttt gaa gag gcc gtg gcc acc 6849 Asn Leu Pro Glu Asp Thr Leu Thr Phe Glu Glu Ala Val Ala Thr 2270 2275 2280 aac tct ggc cgc tcc tcc agg act tcc tat gtg tcc tcc ctc act 6894 Asn Ser Gly Arg Ser Ser Arg Thr Ser Tyr Val Ser Ser Leu Thr 2285 2290 2295 tcc caa tcc cac cct ctc cgc cgt gta ccc aat ggc tac cac tgc 6939 Ser Gln Ser His Pro Leu Arg Arg Val Pro Asn Gly Tyr His Cys 2300 2305 2310 act ttg gga ctc agc acc ggc gtc cgg gcg cgg cac agc tac cac 6984 Thr Leu Gly Leu Ser Thr Gly Val Arg Ala Arg His Ser Tyr His 2315 2320 2325 cac cca gac cag gat cac tgg tgc tag 7011 His Pro Asp Gln Asp His Trp Cys 2330 2335 30 2336 PRT Rattus norvegicus 30 Met Val Arg Phe Gly Asp Glu Leu Gly Gly Arg Tyr Gly Gly Thr Gly 1 5 10 15 Gly Gly Glu Arg Ala Arg Gly Gly Gly Ala Gly Gly Ala Gly Gly Pro 20 25 30 Gly Gln Gly Gly Leu Pro Pro Gly Gln Arg Val Leu Tyr Lys Gln Ser 35 40 45 Ile Ala Gln Arg Ala Arg Thr Met Ala Leu Tyr Asn Pro Ile Pro Val 50 55 60 Lys Gln Asn Cys Phe Thr Val Asn Arg Ser Leu Phe Val Phe Ser Glu 65 70 75 80 Asp Asn Val Val Arg Lys Tyr Ala Lys Arg Ile Thr Glu Trp Pro Pro 85 90 95 Phe Glu Tyr Met Ile Leu Ala Thr Ile Ile Ala Asn Cys Ile Val Leu 100 105 110 Ala Leu Glu Gln His Leu Pro Asp Gly Asp Lys Thr Pro Met Ser Glu 115 120 125 Arg Leu Asp Asp Thr Glu Pro Tyr Phe Ile Gly Ile Phe Cys Phe Glu 130 135 140 Ala Gly Ile Lys Ile Ile Ala Leu Gly Phe Val Phe His Lys Gly Ser 145 150 155 160 Tyr Leu Arg Asn Gly Trp Asn Val Met Asp Phe Val Val Val Leu Thr 165 170 175 Glu Ile Leu Ala Thr Ala Gly Thr Asp Phe Asp Leu Arg Thr Leu Arg 180 185 190 Ala Val Arg Val Leu Arg Pro Leu Lys Leu Val Ser Gly Ile Pro Ser 195 200 205 Leu Gln Val Val Leu Lys Ser Ile Met Lys Ala Met Val Pro Leu Leu 210 215 220 Gln Ile Gly Leu Leu Leu Phe Phe Ala Ile Leu Met Phe Ala Ile Ile 225 230 235 240 Gly Leu Glu Phe Tyr Met Gly Lys Phe His Lys Ala Cys Phe Pro Asn 245 250 255 Ser Thr Asp Ala Glu Pro Val Gly Asp Phe Pro Cys Gly Lys Glu Ala 260 265 270 Pro Ala Arg Leu Cys Asp Ser Asp Thr Glu Cys Arg Glu Tyr Trp Pro 275 280 285 Gly Pro Asn Phe Gly Ile Thr Asn Phe Asp Asn Ile Leu Phe Ala Ile 290 295 300 Leu Thr Val Phe Gln Cys Ile Thr Met Glu Gly Trp Thr Asp Ile Leu 305 310 315 320 Tyr Asn Thr Asn Asp Ala Ala Gly Asn Thr Trp Asn Trp Leu Tyr Phe 325 330 335 Ile Pro Leu Ile Ile Ile Gly Ser Phe Phe Met Leu Asn Leu Val Leu 340 345 350 Gly Val Leu Ser Gly Glu Phe Ala Lys Glu Arg Glu Arg Val Glu Asn 355 360 365 Arg Arg Ala Phe Leu Lys Leu Arg Arg Gln Gln Gln Ile Glu Arg Glu 370 375 380 Leu Asn Gly Tyr Leu Glu Trp Ile Phe Lys Ala Glu Glu Val Met Leu 385 390 395 400 Ala Glu Glu Asp Lys Asn Ala Glu Glu Lys Ser Pro Leu Asp Ala Val 405 410 415 Leu Lys Arg Ala Ala Thr Lys Lys Ser Arg Asn Asp Leu Ile His Ala 420 425 430 Glu Glu Gly Glu Asp Arg Phe Val Asp Leu Cys Ala Ala Gly Ser Pro 435 440 445 Phe Ala Arg Ala Ser Leu Lys Ser Gly Lys Thr Glu Ser Ser Ser Tyr 450 455 460 Phe Arg Arg Lys Glu Lys Met Phe Arg Phe Leu Ile Arg Arg Met Val 465 470 475 480 Lys Ala Gln Ser Phe Tyr Trp Val Val Leu Cys Val Val Ala Leu Asn 485 490 495 Thr Leu Cys Val Ala Met Val His Tyr Asn Gln Pro Gln Arg Leu Thr 500 505 510 Thr Ala Leu Tyr Phe Ala Glu Phe Val Phe Leu Gly Leu Phe Leu Thr 515 520 525 Glu Met Ser Leu Lys Met Tyr Gly Leu Gly Pro Arg Ser Tyr Phe Arg 530 535 540 Ser Ser Phe Asn Cys Phe Asp Phe Gly Val Ile Val Gly Ser Ile Phe 545 550 555 560 Glu Val Val Trp Ala Ala Ile Lys Pro Gly Thr Ser Phe Gly Ile Ser 565 570 575 Val Leu Arg Ala Leu Arg Leu Leu Arg Ile Phe Lys Val Thr Lys Tyr 580 585 590 Trp Asn Ser Leu Arg Asn Leu Val Val Ser Leu Leu Asn Ser Met Lys 595 600 605 Ser Ile Ile Ser Leu Leu Phe Leu Leu Phe Leu Phe Ile Val Val Phe 610 615 620 Ala Leu Leu Gly Met Gln Leu Phe Gly Gly Gln Phe Asn Phe Gln Asp 625 630 635 640 Glu Thr Pro Thr Thr Asn Phe Asp Thr Phe Pro Ala Ala Ile Leu Thr 645 650 655 Val Phe Gln Ile Leu Thr Gly Glu Asp Trp Asn Ala Val Met Tyr His 660 665 670 Gly Ile Glu Ser Gln Gly Gly Val Ser Lys Gly Met Phe Ser Ser Phe 675 680 685 Tyr Phe Ile Val Leu Thr Leu Phe Gly Asn Tyr Thr Leu Leu Asn Val 690 695 700 Phe Leu Ala Ile Ala Val Asp Asn Leu Ala Asn Ala Gln Glu Leu Thr 705 710 715 720 Lys Asp Glu Glu Glu Met Glu Glu Ala Ala Asn Gln Lys Leu Ala Leu 725 730 735 Gln Lys Ala Lys Glu Val Ala Glu Val Ser Pro Met Ser Ala Ala Asn 740 745 750 Ile Ser Ile Ala Ala Arg Gln Gln Asn Ser Ala Lys Ala Arg Ser Val 755 760 765 Trp Glu Gln Arg Ala Ser Gln Leu Arg Leu Gln Asn Leu Arg Ala Ser 770 775 780 Cys Glu Ala Leu Tyr Ser Glu Met Asp Pro Glu Glu Arg Leu Arg Tyr 785 790 795 800 Ala Ser Thr Arg His Val Arg Pro Asp Met Lys Thr His Met Asp Arg 805 810 815 Pro Leu Val Val Glu Pro Gly Arg Asp Gly Leu Arg Gly Pro Ala Gly 820 825 830 Asn Lys Ser Lys Pro Glu Gly Thr Glu Ala Thr Glu Gly Ala Asp Pro 835 840 845 Pro Arg Arg His His Arg His Arg Asp Arg Asp Lys Thr Ser Ala Ser 850 855 860 Thr Pro Ala Gly Gly Glu Gln Asp Arg Thr Asp Cys Pro Lys Ala Glu 865 870 875 880 Ser Thr Glu Thr Gly Ala Arg Glu Glu Arg Ala Arg Pro Arg Arg Ser 885 890 895 His Ser Lys Glu Ala Pro Gly Ala Asp Thr Gln Val Arg Cys Glu Arg 900 905 910 Ser Arg Arg His His Arg Arg Gly Ser Pro Glu Glu Ala Thr Glu Arg 915 920 925 Glu Pro Arg Arg His Arg Ala His Arg His Ala Gln Asp Ser Ser Lys 930 935 940 Glu Gly Lys Glu Gly Thr Ala Pro Val Leu Val Pro Lys Gly Glu Arg 945 950 955 960 Arg Ala Arg His Arg Gly Pro Arg Thr Gly Pro Arg Glu Thr Glu Asn 965 970 975 Ser Glu Glu Pro Thr Arg Arg His Arg Ala Lys His Lys Val Pro Pro 980 985 990 Thr Leu Glu Pro Pro Glu Arg Glu Val Ala Glu Lys Glu Ser Asn Val 995 1000 1005 Val Glu Gly Asp Lys Glu Thr Arg Asn His Gln Pro Lys Glu Pro 1010 1015 1020 Arg Cys Asp Leu Glu Ala Ile Ala Val Thr Gly Val Gly Ser Leu 1025 1030 1035 His Met Leu Pro Ser Thr Cys Leu Gln Lys Val Asp Glu Gln Pro 1040 1045 1050 Glu Asp Ala Asp Asn Gln Arg Asn Val Thr Arg Met Gly Ser Gln 1055 1060 1065 Pro Ser Asp Pro Ser Thr Thr Val His Val Pro Val Thr Leu Thr 1070 1075 1080 Gly Pro Pro Gly Glu Ala Thr Val Val Pro Ser Ala Asn Thr Asp 1085 1090 1095 Leu Glu Gly Gln Ala Glu Gly Lys Lys Glu Ala Glu Ala Asp Asp 1100 1105 1110 Val Leu Arg Arg Gly Pro Arg Pro Ile Val Pro Tyr Ser Ser Met 1115 1120 1125 Phe Cys Leu Ser Pro Thr Asn Leu Leu Arg Arg Phe Cys His Tyr 1130 1135 1140 Ile Val Thr Met Arg Tyr Phe Glu Met Val Ile Leu Val Val Ile 1145 1150 1155 Ala Leu Ser Ser Ile Ala Leu Ala Ala Glu Asp Pro Val Arg Thr 1160 1165 1170 Asp Ser Phe Arg Asn Asn Ala Leu Lys Tyr Met Asp Tyr Ile Phe 1175 1180 1185 Thr Gly Val Phe Thr Phe Glu Met Val Ile Lys Met Ile Asp Leu 1190 1195 1200 Gly Leu Leu Leu His Pro Gly Ala Tyr Phe Arg Asp Leu Trp Asn 1205 1210 1215 Ile Leu Asp Phe Ile Val Val Ser Gly Ala Leu Val Ala Phe Ala 1220 1225 1230 Phe Ser Ser Phe Met Gly Gly Ser Lys Gly Lys Asp Ile Asn Thr 1235 1240 1245 Ile Lys Ser Leu Arg Val Leu Arg Val Leu Arg Pro Leu Lys Thr 1250 1255 1260 Ile Lys Arg Leu Pro Lys Leu Lys Ala Val Phe Asp Cys Val Val 1265 1270 1275 Asn Ser Leu Lys Asn Val Leu Asn Ile Leu Ile Val Tyr Met Leu 1280 1285 1290 Phe Met Phe Ile Phe Ala Val Ile Ala Val Gln Leu Phe Lys Gly 1295 1300 1305 Lys Phe Phe Tyr Cys Thr Asp Glu Ser Lys Glu Leu Glu Arg Asp 1310 1315 1320 Cys Arg Gly Gln Tyr Leu Asp Tyr Glu Lys Glu Glu Val Glu Ala 1325 1330 1335 Gln Pro Arg Gln Trp Lys Lys Tyr Asp Phe His Tyr Asp Asn Val 1340 1345 1350 Leu Trp Ala Leu Leu Thr Leu Phe Thr Val Ser Thr Gly Glu Gly 1355 1360 1365 Trp Pro Met Val Leu Lys His Ser Val Asp Ala Thr Tyr Glu Glu 1370 1375 1380 Gln Gly Pro Ser Pro Gly Phe Arg Met Glu Leu Ser Ile Phe Tyr 1385 1390 1395 Val Val Tyr Phe Val Val Phe Pro Phe Phe Phe Val Asn Ile Phe 1400 1405 1410 Val Ala Leu Ile Ile Ile Thr Phe Gln Glu Gln Gly Asp Lys Val 1415 1420 1425 Met Ser Glu Cys Ser Leu Glu Lys Asn Glu Arg Ala Cys Ile Asp 1430 1435 1440 Phe Ala Ile Ser Ala Lys Pro Leu Thr Arg Tyr Met Pro Gln Asn 1445 1450 1455 Lys Gln Ser Phe Gln Tyr Lys Thr Trp Thr Phe Val Val Ser Pro 1460 1465 1470 Pro Phe Glu Tyr Phe Ile Met Ala Met Ile Ala Leu Asn Thr Val 1475 1480 1485 Val Leu Met Met Lys Phe Tyr Asp Ala Pro Tyr Glu Tyr Glu Leu 1490 1495 1500 Met Leu Lys Cys Leu Asn Ile Val Phe Thr Ser Met Phe Ser Leu 1505 1510 1515 Glu Cys Ile Leu Lys Ile Ile Ala Phe Gly Val Leu Asn Tyr Phe 1520 1525 1530 Arg Asp Ala Trp Asn Val Phe Asp Phe Val Thr Val Leu Gly Ser 1535 1540 1545 Ile Thr Asp Ile Leu Val Thr Glu Ile Ala Asn Asn Phe Ile Asn 1550 1555 1560 Leu Ser Phe Leu Arg Leu Phe Arg Ala Ala Arg Leu Ile Lys Leu 1565 1570 1575 Cys Arg Gln Gly Tyr Thr Ile Arg Ile Leu Leu Trp Thr Phe Val 1580 1585 1590 Gln Ser Phe Lys Ala Leu Pro Tyr Val Cys Leu Leu Ile Ala Met 1595 1600 1605 Leu Phe Phe Ile Tyr Ala Ile Ile Gly Met Gln Val Phe Gly Asn 1610 1615 1620 Ile Ala Leu Asp Asp Gly Thr Ser Ile Asn Arg His Asn Asn Phe 1625 1630 1635 Arg Thr Phe Leu Gln Ala Leu Met Leu Leu Phe Arg Ser Ala Thr 1640 1645 1650 Gly Glu Ala Trp His Glu Ile Met Leu Ser Cys Leu Gly Asn Arg 1655 1660 1665 Ala Cys Asp Pro His Ala Asn Ala Ser Glu Cys Gly Ser Asp Phe 1670 1675 1680 Ala Tyr Phe Tyr Phe Val Ser Phe Ile Phe Leu Cys Ser Phe Leu 1685 1690 1695 Met Leu Asn Leu Phe Val Ala Val Ile Met Asp Asn Phe Glu Tyr 1700 1705 1710 Leu Thr Arg Asp Ser Ser Ile Leu Gly Pro His His Leu Asp Glu 1715 1720 1725 Phe Ile Arg Val Trp Ala Glu Tyr Asp Pro Ala Ala Cys Gly Arg 1730 1735 1740 Ile Ser Tyr Asn Asp Met Phe Glu Met Leu Lys His Met Ser Pro 1745 1750 1755 Pro Leu Gly Leu Gly Lys Lys Cys Pro Ala Arg Val Ala Tyr Lys 1760 1765 1770 Arg Leu Val Arg Met Asn Met Pro Ile Ser Asn Glu Asp Met Thr 1775 1780 1785 Val His Phe Thr Ser Thr Leu Met Ala Leu Ile Arg Thr Ala Leu 1790 1795 1800 Glu Ile Lys Leu Ala Pro Ala Gly Thr Lys Gln His Gln Cys Asp 1805 1810 1815 Ala Glu Leu Arg Lys Glu Ile Ser Ser Val Trp Ala Asn Leu Pro 1820 1825 1830 Gln Lys Thr Leu Asp Leu Leu Val Pro Pro His Lys Pro Asp Glu 1835 1840 1845 Met Thr Val Gly Lys Val Tyr Ala Ala Leu Met Ile Phe Asp Phe 1850 1855 1860 Tyr Lys Gln Asn Lys Thr Thr Arg Asp Gln Thr His Gln Ala Pro 1865 1870 1875 Gly Gly Leu Ser Gln Met Gly Pro Val Ser Leu Phe His Pro Leu 1880 1885 1890 Lys Ala Thr Leu Glu Gln Thr Gln Pro Ala Val Leu Arg Gly Ala 1895 1900 1905 Arg Val Phe Leu Arg Gln Lys Ser Ala Thr Ser Leu Ser Asn Gly 1910 1915 1920 Gly Ala Ile Gln Thr Gln Glu Ser Gly Ile Lys Glu Ser Leu Ser 1925 1930 1935 Trp Gly Thr Gln Arg Thr Gln Asp Val Leu Tyr Glu Ala Arg Ala 1940 1945 1950 Pro Leu Glu Arg Gly His Ser Ala Glu Ile Pro Val Gly Gln Pro 1955 1960 1965 Gly Ala Leu Ala Val Asp Val Gln Met Gln Asn Met Thr Leu Arg 1970 1975 1980 Gly Pro Asp Gly Glu Pro Gln Pro Gly Leu Glu Ser Gln Gly Arg 1985 1990 1995 Ala Ala Ser Met Pro Arg Leu Ala Ala Glu Thr Gln Pro Ala Pro 2000 2005 2010 Asn Ala Ser Pro Met Lys Arg Ser Ile Ser Thr Leu Ala Pro Arg 2015 2020 2025 Pro His Gly Thr Gln Leu Cys Asn Thr Val Leu Asp Arg Pro Pro 2030 2035 2040 Pro Ser Gln Val Ser His His His His His Arg Cys His Arg Arg 2045 2050 2055 Arg Asp Lys Lys Gln Arg Ser Leu Glu Lys Gly Pro Ser Leu Ser 2060 2065 2070 Val Asp Thr Glu Gly Ala Pro Ser Thr Ala Ala Gly Ser Gly Leu 2075 2080 2085 Pro His Gly Glu Gly Ser Thr Gly Cys Arg Arg Glu Arg Lys Gln 2090 2095 2100 Glu Arg Gly Arg Ser Gln Glu Arg Arg Gln Pro Ser Ser Ser Ser 2105 2110 2115 Ser Glu Lys Gln Arg Phe Tyr Ser Cys Asp Arg Phe Gly Ser Arg 2120 2125 2130 Glu Pro Pro Gln Pro Lys Pro Ser Leu Ser Ser His Pro Ile Ser 2135 2140 2145 Pro Thr Ala Ala Leu Glu Pro Gly Pro His Pro Gln Gly Ser Gly 2150 2155 2160 Ser Val Asn Gly Ser Pro Leu Met Ser Thr Ser Gly Ala Ser Thr 2165 2170 2175 Pro Gly Arg Gly Gly Arg Arg Gln Leu Pro Gln Thr Pro Leu Thr 2180 2185 2190 Pro Arg Pro Ser Ile Thr Tyr Lys Thr Ala Asn Ser Ser Pro Val 2195 2200 2205 His Phe Ala Glu Gly Gln Ser Gly Leu Pro Ala Phe Ser Pro Gly 2210 2215 2220 Arg Leu Ser Arg Gly Leu Ser Glu His Asn Ala Leu Leu Gln Lys 2225 2230 2235 Glu Pro Leu Ser Gln Pro Leu Ala Ser Gly Ser Arg Ile Gly Ser 2240 2245 2250 Asp Pro Tyr Leu Gly Gln Arg Leu Asp Ser Glu Ala Ser Ala His 2255 2260 2265 Asn Leu Pro Glu Asp Thr Leu Thr Phe Glu Glu Ala Val Ala Thr 2270 2275 2280 Asn Ser Gly Arg Ser Ser Arg Thr Ser Tyr Val Ser Ser Leu Thr 2285 2290 2295 Ser Gln Ser His Pro Leu Arg Arg Val Pro Asn Gly Tyr His Cys 2300 2305 2310 Thr Leu Gly Leu Ser Thr Gly Val Arg Ala Arg His Ser Tyr His 2315 2320 2325 His Pro Asp Gln Asp His Trp Cys 2330 2335 31 7364 DNA Homo sapiens CDS (146)..(7165) 31 gcggcggcgg ctgcggcggt ggggccgggc gaggtccgct gcggtcccgg cggctccgtg 60 gctgctccgc tctgagcgcc tggcgcgccc cgcgccctcc ctgccggggc cgctgggccg 120 gggatgcacg cggggcccgg gagcc atg gtc cgc ttc ggg gac gag ctg ggc 172 Met Val Arg Phe Gly Asp Glu Leu Gly 1 5 ggc cgc tat gga ggc ccc ggc ggc gga gag cgg gcc cgg ggc ggc ggg 220 Gly Arg Tyr Gly Gly Pro Gly Gly Gly Glu Arg Ala Arg Gly Gly Gly 10 15 20 25 gcc ggc ggg gcg ggg ggc ccg ggt ccc ggg ggg ctg cag ccc ggc cag 268 Ala Gly Gly Ala Gly Gly Pro Gly Pro Gly Gly Leu Gln Pro Gly Gln 30 35 40 cgg gtc ctc tac aag caa tcg atc gcg cag cgc gcg cgg acc atg gcg 316 Arg Val Leu Tyr Lys Gln Ser Ile Ala Gln Arg Ala Arg Thr Met Ala 45 50 55 ctg tac aac ccc atc ccg gtc aag cag aac tgc ttc acc gtc aac cgc 364 Leu Tyr Asn Pro Ile Pro Val Lys Gln Asn Cys Phe Thr Val Asn Arg 60 65 70 tcg ctc ttc gtc ttc agc gag gac aac gtc gtc cgc aaa tac gcg aag 412 Ser Leu Phe Val Phe Ser Glu Asp Asn Val Val Arg Lys Tyr Ala Lys 75 80 85 cgc atc acc gag tgg cct cca ttc gag tat atg atc ctg gcc acc atc 460 Arg Ile Thr Glu Trp Pro Pro Phe Glu Tyr Met Ile Leu Ala Thr Ile 90 95 100 105 atc gcc aac tgc atc gtg ctg gcc ctg gag cag cac ctc cct gat ggg 508 Ile Ala Asn Cys Ile Val Leu Ala Leu Glu Gln His Leu Pro Asp Gly 110 115 120 gac aaa acg ccc atg tcc gag cgg ctg gac gac acg gag ccc tat ttc 556 Asp Lys Thr Pro Met Ser Glu Arg Leu Asp Asp Thr Glu Pro Tyr Phe 125 130 135 atc ggg atc ttt tgc ttc gag gca ggg atc aaa atc atc gct ctg ggc 604 Ile Gly Ile Phe Cys Phe Glu Ala Gly Ile Lys Ile Ile Ala Leu Gly 140 145 150 ttt gtc ttc cac aag ggc tct tac ctg cgg aac ggc tgg aac gtc atg 652 Phe Val Phe His Lys Gly Ser Tyr Leu Arg Asn Gly Trp Asn Val Met 155 160 165 gac ttc gtg gtc gtc ctc aca ggg atc ctt gcc acg gct gga act gac 700 Asp Phe Val Val Val Leu Thr Gly Ile Leu Ala Thr Ala Gly Thr Asp 170 175 180 185 ttc gac ctg cga aca ctg agg gct gtg cgt gtg ctg agg ccc ctg aag 748 Phe Asp Leu Arg Thr Leu Arg Ala Val Arg Val Leu Arg Pro Leu Lys 190 195 200 ctg gtg tct ggg att cca agt ttg cag gtg gtg ctc aag tcc atc atg 796 Leu Val Ser Gly Ile Pro Ser Leu Gln Val Val Leu Lys Ser Ile Met 205 210 215 aag gcc atg gtt cca ctc ctg cag att ggg ctg ctt ctc ttc ttt gcc 844 Lys Ala Met Val Pro Leu Leu Gln Ile Gly Leu Leu Leu Phe Phe Ala 220 225 230 atc ctc atg ttt gcc atc att ggc ctg gag ttc tac atg ggc aag ttc 892 Ile Leu Met Phe Ala Ile Ile Gly Leu Glu Phe Tyr Met Gly Lys Phe 235 240 245 cac aag gcc tgt ttc ccc aac agc aca gat gcg gag ccc gtg ggt gac 940 His Lys Ala Cys Phe Pro Asn Ser Thr Asp Ala Glu Pro Val Gly Asp 250 255 260 265 ttc ccc tgt ggc aag gag gcc cca gcc cgg ctg tgc gag ggc gac act 988 Phe Pro Cys Gly Lys Glu Ala Pro Ala Arg Leu Cys Glu Gly Asp Thr 270 275 280 gag tgc cgg gag tac tgg cca gga ccc aac ttt ggc atc acc aac ttt 1036 Glu Cys Arg Glu Tyr Trp Pro Gly Pro Asn Phe Gly Ile Thr Asn Phe 285 290 295 gac aat atc ctg ttt gcc atc ttg acg gtg ttc cag tgc atc acc atg 1084 Asp Asn Ile Leu Phe Ala Ile Leu Thr Val Phe Gln Cys Ile Thr Met 300 305 310 gag ggc tgg act gac atc ctc tat aat aca aac gat gcg gcc ggc aac 1132 Glu Gly Trp Thr Asp Ile Leu Tyr Asn Thr Asn Asp Ala Ala Gly Asn 315 320 325 acc tgg aac tgg ctc tac ttc atc cct ctc atc atc atc ggc tcc ttc 1180 Thr Trp Asn Trp Leu Tyr Phe Ile Pro Leu Ile Ile Ile Gly Ser Phe 330 335 340 345 ttc atg ctc aac ctg gtg ctg ggc gtg ctc tcg ggg gag ttt gcc aag 1228 Phe Met Leu Asn Leu Val Leu Gly Val Leu Ser Gly Glu Phe Ala Lys 350 355 360 gag cga gag agg gtg gag aac cgc cgc gcc ttc ctg aag ctg cgc cgg 1276 Glu Arg Glu Arg Val Glu Asn Arg Arg Ala Phe Leu Lys Leu Arg Arg 365 370 375 cag cag cag atc gag cga gag ctc aac ggg tac ctg gag tgg atc ttc 1324 Gln Gln Gln Ile Glu Arg Glu Leu Asn Gly Tyr Leu Glu Trp Ile Phe 380 385 390 aag gcg gag gaa gtc atg ctg gcc gag gag gac agg aat gca gag gag 1372 Lys Ala Glu Glu Val Met Leu Ala Glu Glu Asp Arg Asn Ala Glu Glu 395 400 405 aag tcc cct ttg gac gtg ctg aag aga gcg gcc acc aag aag agc aga 1420 Lys Ser Pro Leu Asp Val Leu Lys Arg Ala Ala Thr Lys Lys Ser Arg 410 415 420 425 aat gac ctg atc cac gca gag gag gga gag gac cgg ttt gca gat ctc 1468 Asn Asp Leu Ile His Ala Glu Glu Gly Glu Asp Arg Phe Ala Asp Leu 430 435 440 tgt gct gtt gga tcc ccc ttc gcc cgc gcc agc ctc aag agc ggg aag 1516 Cys Ala Val Gly Ser Pro Phe Ala Arg Ala Ser Leu Lys Ser Gly Lys 445 450 455 aca gag agc tcg tca tac ttc cgg agg aag gag aag atg ttc cgg ttt 1564 Thr Glu Ser Ser Ser Tyr Phe Arg Arg Lys Glu Lys Met Phe Arg Phe 460 465 470 ttt atc cgg cgc atg gtg aag gct cag agc ttc tac tgg gtg gtg ctg 1612 Phe Ile Arg Arg Met Val Lys Ala Gln Ser Phe Tyr Trp Val Val Leu 475 480 485 tgc gtg gtg gcc ctg aac aca ctg tgt gtg gcc atg gtg cat tac aac 1660 Cys Val Val Ala Leu Asn Thr Leu Cys Val Ala Met Val His Tyr Asn 490 495 500 505 cag ccg cgg cgg ctt acc acg acc ctg tat ttt gca gag ttt gtt ttc 1708 Gln Pro Arg Arg Leu Thr Thr Thr Leu Tyr Phe Ala Glu Phe Val Phe 510 515 520 ctg ggt ctc ttc ctc aca gag atg tcc ctg aag atg tat ggc ctg ggg 1756 Leu Gly Leu Phe Leu Thr Glu Met Ser Leu Lys Met Tyr Gly Leu Gly 525 530 535 ccc aga agc tac ttc cgg tcc tcc ttc aac tgc ttc gac ttt ggg gtc 1804 Pro Arg Ser Tyr Phe Arg Ser Ser Phe Asn Cys Phe Asp Phe Gly Val 540 545 550 atc gtg ggg agc gtc ttt gaa gtg gtc tgg gcg gcc atc aag ccg gga 1852 Ile Val Gly Ser Val Phe Glu Val Val Trp Ala Ala Ile Lys Pro Gly 555 560 565 agc tcc ttt ggg atc agt gtg ctg cgg gcc ctc cgc ctg ctg agg atc 1900 Ser Ser Phe Gly Ile Ser Val Leu Arg Ala Leu Arg Leu Leu Arg Ile 570 575 580 585 ttc aaa gtc acg aag tac tgg agc tcc ctg cgg aac ctg gtg gtg tcc 1948 Phe Lys Val Thr Lys Tyr Trp Ser Ser Leu Arg Asn Leu Val Val Ser 590 595 600 ctg ctg aac tcc atg aag tcc atc atc agc ctg ctc ttc ttg ctc ttc 1996 Leu Leu Asn Ser Met Lys Ser Ile Ile Ser Leu Leu Phe Leu Leu Phe 605 610 615 ctg ttc att gtg gtc ttc gcc ctg ctg ggg atg cag ctg ttt ggg gga 2044 Leu Phe Ile Val Val Phe Ala Leu Leu Gly Met Gln Leu Phe Gly Gly 620 625 630 cag ttc aac ttc cag gat gag act ccc aca acc aac ttc gac acc ttc 2092 Gln Phe Asn Phe Gln Asp Glu Thr Pro Thr Thr Asn Phe Asp Thr Phe 635 640 645 cct gcc gcc atc ctc act gtc ttc cag atc ctg acg gga gag gac tgg 2140 Pro Ala Ala Ile Leu Thr Val Phe Gln Ile Leu Thr Gly Glu Asp Trp 650 655 660 665 aat gca gtg atg tat cac ggg atc gaa tcg caa ggc ggc gtc agc aaa 2188 Asn Ala Val Met Tyr His Gly Ile Glu Ser Gln Gly Gly Val Ser Lys 670 675 680 ggc atg ttc tcg tcc ttt tac ttc att gtc ctg aca ctg ttc gga aac 2236 Gly Met Phe Ser Ser Phe Tyr Phe Ile Val Leu Thr Leu Phe Gly Asn 685 690 695 tac act ctg ctg aat gtc ttt ctg gcc atc gct gtg gac aac ctg gcc 2284 Tyr Thr Leu Leu Asn Val Phe Leu Ala Ile Ala Val Asp Asn Leu Ala 700 705 710 aac gcc caa gag ctg acc aag gat gaa gag gag atg gaa gaa gca gcc 2332 Asn Ala Gln Glu Leu Thr Lys Asp Glu Glu Glu Met Glu Glu Ala Ala 715 720 725 aat cag aag ctt gct ctg caa aag gcc aaa gaa gtg gct gaa gtc agc 2380 Asn Gln Lys Leu Ala Leu Gln Lys Ala Lys Glu Val Ala Glu Val Ser 730 735 740 745 ccc atg tct gcc gcg aac atc tcc atc gcc gcc agg cag cag aac tcg 2428 Pro Met Ser Ala Ala Asn Ile Ser Ile Ala Ala Arg Gln Gln Asn Ser 750 755 760 gcc aag gcg cgc tcg gtg tgg gag cag cgg gcc agc cag cta cgg ctg 2476 Ala Lys Ala Arg Ser Val Trp Glu Gln Arg Ala Ser Gln Leu Arg Leu 765 770 775 cag aac ctg cgg gcc agc tgc gag gcg ctg tac agc gag atg gac ccc 2524 Gln Asn Leu Arg Ala Ser Cys Glu Ala Leu Tyr Ser Glu Met Asp Pro 780 785 790 gag gag cgg ctg cgc ttc gcc act acg cgc cac ctg cgg ccc gac atg 2572 Glu Glu Arg Leu Arg Phe Ala Thr Thr Arg His Leu Arg Pro Asp Met 795 800 805 aag acg cac ctg gac cgg ccg ctg gtg gtg gag ctg ggc cgc gac ggc 2620 Lys Thr His Leu Asp Arg Pro Leu Val Val Glu Leu Gly Arg Asp Gly 810 815 820 825 gcg cgg ggg ccc gtg gga ggc aaa gcc cga cct gag gct gcg gag gcc 2668 Ala Arg Gly Pro Val Gly Gly Lys Ala Arg Pro Glu Ala Ala Glu Ala 830 835 840 ccc gag ggc gtc gac cct ccg cgc agg cac cac cgg cac cgc gac aag 2716 Pro Glu Gly Val Asp Pro Pro Arg Arg His His Arg His Arg Asp Lys 845 850 855 gac aag acc ccc gcg gcg ggg gac cag gac cga gca gag gcc ccg aag 2764 Asp Lys Thr Pro Ala Ala Gly Asp Gln Asp Arg Ala Glu Ala Pro Lys 860 865 870 gcg gag agc ggg gag ccc ggt gcc cgg gag gag cgg ccg cgg ccg cac 2812 Ala Glu Ser Gly Glu Pro Gly Ala Arg Glu Glu Arg Pro Arg Pro His 875 880 885 cgc agc cac agc aag gag gcc gcg ggg ccc ccg gag gcg cgg agc gag 2860 Arg Ser His Ser Lys Glu Ala Ala Gly Pro Pro Glu Ala Arg Ser Glu 890 895 900 905 cgc ggc cga ggc cca ggc ccc gag ggc ggc cgg cgg cac cac cgg cgc 2908 Arg Gly Arg Gly Pro Gly Pro Glu Gly Gly Arg Arg His His Arg Arg 910 915 920 ggc tcc ccg gag gag gcg gcc gag cgg gag ccc cga cgc cac cgc gcg 2956 Gly Ser Pro Glu Glu Ala Ala Glu Arg Glu Pro Arg Arg His Arg Ala 925 930 935 cac cgg cac cag gat ccg agc aag gag tgc gcc ggc gcc aag ggc gag 3004 His Arg His Gln Asp Pro Ser Lys Glu Cys Ala Gly Ala Lys Gly Glu 940 945 950 cgg cgc gcg cgg cac cgc ggc ggc ccc cga gcg ggg ccc cgg gag gcg 3052 Arg Arg Ala Arg His Arg Gly Gly Pro Arg Ala Gly Pro Arg Glu Ala 955 960 965 gag agc ggg gag gag ccg gcg cgg cgg cac cgg gcc cgg cac aag gcg 3100 Glu Ser Gly Glu Glu Pro Ala Arg Arg His Arg Ala Arg His Lys Ala 970 975 980 985 cag cct gct cac gag gct gtg gag aag gag acc acg gag aag gag gcc 3148 Gln Pro Ala His Glu Ala Val Glu Lys Glu Thr Thr Glu Lys Glu Ala 990 995 1000 acg gag aag gag gct gag ata gtg gaa gcc gac aag gaa aag gag 3193 Thr Glu Lys Glu Ala Glu Ile Val Glu Ala Asp Lys Glu Lys Glu 1005 1010 1015 ctc cgg aac cac cag ccc cgg gag cca cac tgt gac ctg gag acc 3238 Leu Arg Asn His Gln Pro Arg Glu Pro His Cys Asp Leu Glu Thr 1020 1025 1030 agt ggg act gtg act gtg ggt ccc atg cac aca ctg ccc agc acc 3283 Ser Gly Thr Val Thr Val Gly Pro Met His Thr Leu Pro Ser Thr 1035 1040 1045 tgt ctc cag aag gtg gag gaa cag cca gag gat gca gac aat cag 3328 Cys Leu Gln Lys Val Glu Glu Gln Pro Glu Asp Ala Asp Asn Gln 1050 1055 1060 cgg aac gtc act cgc atg ggc agt cag ccc cca gac ccg aac act 3373 Arg Asn Val Thr Arg Met Gly Ser Gln Pro Pro Asp Pro Asn Thr 1065 1070 1075 att gta cat atc cca gtg atg ctg acg ggc cct ctt ggg gaa gcc 3418 Ile Val His Ile Pro Val Met Leu Thr Gly Pro Leu Gly Glu Ala 1080 1085 1090 acg gtc gtt ccc agt ggt aac gtg gac ctg gaa agc caa gca gag 3463 Thr Val Val Pro Ser Gly Asn Val Asp Leu Glu Ser Gln Ala Glu 1095 1100 1105 ggg aag aag gag gtg gaa gcg gat gac gtg atg agg agc ggc ccc 3508 Gly Lys Lys Glu Val Glu Ala Asp Asp Val Met Arg Ser Gly Pro 1110 1115 1120 cgg cct atc gtc cca tac agc tcc atg ttc tgt tta agc ccc acc 3553 Arg Pro Ile Val Pro Tyr Ser Ser Met Phe Cys Leu Ser Pro Thr 1125 1130 1135 aac ctg ctc cgc cgc ttc tgc cac tac atc gtg acc atg agg tac 3598 Asn Leu Leu Arg Arg Phe Cys His Tyr Ile Val Thr Met Arg Tyr 1140 1145 1150 ttc gag gtg gtc att ctc gtg gtc atc gcc ttg agc agc atc gcc 3643 Phe Glu Val Val Ile Leu Val Val Ile Ala Leu Ser Ser Ile Ala 1155 1160 1165 ctg gct gct gag gac cca gtg cgc aca gac tcg ccc agg aac aac 3688 Leu Ala Ala Glu Asp Pro Val Arg Thr Asp Ser Pro Arg Asn Asn 1170 1175 1180 gct ctg aaa tac ctg gat tac att ttc act ggt gtc ttt acc ttt 3733 Ala Leu Lys Tyr Leu Asp Tyr Ile Phe Thr Gly Val Phe Thr Phe 1185 1190 1195 gag atg gtg ata aag atg atc gac ttg gga ctg ctg ctt cac cct 3778 Glu Met Val Ile Lys Met Ile Asp Leu Gly Leu Leu Leu His Pro 1200 1205 1210 gga gcc tat ttc cgg gac ttg tgg aac att ctg gac ttc att gtg 3823 Gly Ala Tyr Phe Arg Asp Leu Trp Asn Ile Leu Asp Phe Ile Val 1215 1220 1225 gtc agt ggc gcc ctg gtg gcg ttt gct ttc tca gga tcc aaa ggg 3868 Val Ser Gly Ala Leu Val Ala Phe Ala Phe Ser Gly Ser Lys Gly 1230 1235 1240 aaa gac atc aat acc atc aag tct ctg aga gtc ctt cgt gtc ctg 3913 Lys Asp Ile Asn Thr Ile Lys Ser Leu Arg Val Leu Arg Val Leu 1245 1250 1255 cgg ccc ctc aag acc atc aaa cgg ctg ccc aag ctc aag gct gtg 3958 Arg Pro Leu Lys Thr Ile Lys Arg Leu Pro Lys Leu Lys Ala Val 1260 1265 1270 ttt gac tgt gtg gtg aac tcc ctg aag aat gtc ctc aac atc ttg 4003 Phe Asp Cys Val Val Asn Ser Leu Lys Asn Val Leu Asn Ile Leu 1275 1280 1285 att gtc tac atg ctc ttc atg ttc ata ttt gcc gtc att gcg gtg 4048 Ile Val Tyr Met Leu Phe Met Phe Ile Phe Ala Val Ile Ala Val 1290 1295 1300 cag ctc ttc aaa ggg aag ttt ttc tac tgc aca gat gaa tcc aag 4093 Gln Leu Phe Lys Gly Lys Phe Phe Tyr Cys Thr Asp Glu Ser Lys 1305 1310 1315 gag ctg gag agg gac tgc agg ggt cag tat ttg gat tat gag aag 4138 Glu Leu Glu Arg Asp Cys Arg Gly Gln Tyr Leu Asp Tyr Glu Lys 1320 1325 1330 gag gaa gtg gaa gct cag ccc agg cag tgg aag aaa tac gac ttt 4183 Glu Glu Val Glu Ala Gln Pro Arg Gln Trp Lys Lys Tyr Asp Phe 1335 1340 1345 cac tac gac aat gtg ctc tgg gct ctg ctg acg ctg ttc aca gtg 4228 His Tyr Asp Asn Val Leu Trp Ala Leu Leu Thr Leu Phe Thr Val 1350 1355 1360 tcc acg gga gaa ggc tgg ccc atg gtg ctg aaa cac tcc gtg gat 4273 Ser Thr Gly Glu Gly Trp Pro Met Val Leu Lys His Ser Val Asp 1365 1370 1375 gcc acc tat gag gag cag ggt cca agc cct ggg tac cgc atg gag 4318 Ala Thr Tyr Glu Glu Gln Gly Pro Ser Pro Gly Tyr Arg Met Glu 1380 1385 1390 ctg tcc atc ttc tac gtg gtc tac ttt gtg gtc ttt ccc ttc ttc 4363 Leu Ser Ile Phe Tyr Val Val Tyr Phe Val Val Phe Pro Phe Phe 1395 1400 1405 ttc gtc aac atc ttt gtg gct ttg atc atc atc acc ttc cag gag 4408 Phe Val Asn Ile Phe Val Ala Leu Ile Ile Ile Thr Phe Gln Glu 1410 1415 1420 cag ggg gac aag gtg atg tct gaa tgc agc ctg gag aag aac gag 4453 Gln Gly Asp Lys Val Met Ser Glu Cys Ser Leu Glu Lys Asn Glu 1425 1430 1435 agg gct tgc att gac ttc gcc atc agc gcc aaa ccc ctg aca cgg 4498 Arg Ala Cys Ile Asp Phe Ala Ile Ser Ala Lys Pro Leu Thr Arg 1440 1445 1450 tac atg ccc caa aac cgg cag tcg ttc cag tat aag acg tgg aca 4543 Tyr Met Pro Gln Asn Arg Gln Ser Phe Gln Tyr Lys Thr Trp Thr 1455 1460 1465 ttt gtg gtc tcc ccg ccc ttt gaa tac ttc atc atg gcc atg ata 4588 Phe Val Val Ser Pro Pro Phe Glu Tyr Phe Ile Met Ala Met Ile 1470 1475 1480 gcc ctc aac act gtg gtg ctg atg atg aag ttc tat gat gca ccc 4633 Ala Leu Asn Thr Val Val Leu Met Met Lys Phe Tyr Asp Ala Pro 1485 1490 1495 tat gag tac gag ctg atg ctg aaa tgc ctg aac atc gtg ttc aca 4678 Tyr Glu Tyr Glu Leu Met Leu Lys Cys Leu Asn Ile Val Phe Thr 1500 1505 1510 tcc atg ttc tcc atg gaa tgc gtg ctg aag atc atc gcc ttt ggg 4723 Ser Met Phe Ser Met Glu Cys Val Leu Lys Ile Ile Ala Phe Gly 1515 1520 1525 gtg ctg aac tat ttc aga gat gcc tgg aat gtc ttt gac ttt gtc 4768 Val Leu Asn Tyr Phe Arg Asp Ala Trp Asn Val Phe Asp Phe Val 1530 1535 1540 act gtg ttg gga agt att act gat att tta gta aca gag att gcg 4813 Thr Val Leu Gly Ser Ile Thr Asp Ile Leu Val Thr Glu Ile Ala 1545 1550 1555 gaa acg aac aat ttc atc aac ctc agc ttc ctc cgc ctc ttt cga 4858 Glu Thr Asn Asn Phe Ile Asn Leu Ser Phe Leu Arg Leu Phe Arg 1560 1565 1570 gct gcg cgg ctg atc aag ctg ctc cgc cag ggc tac acc atc cgc 4903 Ala Ala Arg Leu Ile Lys Leu Leu Arg Gln Gly Tyr Thr Ile Arg 1575 1580 1585 atc ctg ctg tgg acc ttt gtc cag tcc ttc aag gcc ctg ccc tac 4948 Ile Leu Leu Trp Thr Phe Val Gln Ser Phe Lys Ala Leu Pro Tyr 1590 1595 1600 gtg tgt ctg ctc att gcc atg ctg ttc ttc atc tac gcc atc atc 4993 Val Cys Leu Leu Ile Ala Met Leu Phe Phe Ile Tyr Ala Ile Ile 1605 1610 1615 ggc atg cag gtg ttt ggg aat att gcc ctg gat gat gac acc agc 5038 Gly Met Gln Val Phe Gly Asn Ile Ala Leu Asp Asp Asp Thr Ser 1620 1625 1630 atc aac cgc cac aac aac ttc cgg acg ttt ttg caa gcc ctg atg 5083 Ile Asn Arg His Asn Asn Phe Arg Thr Phe Leu Gln Ala Leu Met 1635 1640 1645 ctg ctg ttc agg agc gcc acg ggg gag gcc tgg cac gag atc atg 5128 Leu Leu Phe Arg Ser Ala Thr Gly Glu Ala Trp His Glu Ile Met 1650 1655 1660 ctg tcc tgc ctg agc aac cag gcc tgt gat gag cag gcc aat gcc 5173 Leu Ser Cys Leu Ser Asn Gln Ala Cys Asp Glu Gln Ala Asn Ala 1665 1670 1675 acc gag tgt gga agt gac ttt gcc tac ttc tac ttc gtc tcc ttc 5218 Thr Glu Cys Gly Ser Asp Phe Ala Tyr Phe Tyr Phe Val Ser Phe 1680 1685 1690 atc ttc ctg tgc tcc ttt ctg atg ttg aac ctc ttt gtg gct gtg 5263 Ile Phe Leu Cys Ser Phe Leu Met Leu Asn Leu Phe Val Ala Val 1695 1700 1705 atc atg gac aat ttt gag tac ctc acg cgg gac tct tcc atc cta 5308 Ile Met Asp Asn Phe Glu Tyr Leu Thr Arg Asp Ser Ser Ile Leu 1710 1715 1720 ggt cct cac cac ttg gat gag ttc atc cgg gtc tgg gct gaa tac 5353 Gly Pro His His Leu Asp Glu Phe Ile Arg Val Trp Ala Glu Tyr 1725 1730 1735 gac ccg gct gcg tgt ggg cgc atc agt tac aat gac atg ttt gag 5398 Asp Pro Ala Ala Cys Gly Arg Ile Ser Tyr Asn Asp Met Phe Glu 1740 1745 1750 atg ctg aaa cac atg tcc ccg cct ctg ggg ctg ggg aag aaa tgc 5443 Met Leu Lys His Met Ser Pro Pro Leu Gly Leu Gly Lys Lys Cys 1755 1760 1765 cct gct cga gtt gct tac aag cgc ctg gtt cgc atg aac atg ccc 5488 Pro Ala Arg Val Ala Tyr Lys Arg Leu Val Arg Met Asn Met Pro 1770 1775 1780 atc tcc aac gag gac atg act gtt cac ttc acg tcc acg ctg atg 5533 Ile Ser Asn Glu Asp Met Thr Val His Phe Thr Ser Thr Leu Met 1785 1790 1795 gcc ctc atc cgg acg gca ctg gag atc aag ctg gcc cca gct ggg 5578 Ala Leu Ile Arg Thr Ala Leu Glu Ile Lys Leu Ala Pro Ala Gly 1800 1805 1810 aca aag cag cat cag tgt gac gcg gag ttg agg aag gag att tcc 5623 Thr Lys Gln His Gln Cys Asp Ala Glu Leu Arg Lys Glu Ile Ser 1815 1820 1825 gtt gtg tgg gcc aat ctg ccc cag aag act ttg gac ttg ctg gta 5668 Val Val Trp Ala Asn Leu Pro Gln Lys Thr Leu Asp Leu Leu Val 1830 1835 1840 cca ccc cat aag cct gat gag atg aca gtg ggg aag gtt tat gca 5713 Pro Pro His Lys Pro Asp Glu Met Thr Val Gly Lys Val Tyr Ala 1845 1850 1855 gct ctg atg ata ttt gac ttc tac aag cag aac aaa acc acc aga 5758 Ala Leu Met Ile Phe Asp Phe Tyr Lys Gln Asn Lys Thr Thr Arg 1860 1865 1870 gac cag atg cag cag gct cct gga ggc ctc tcc cag atg ggt cct 5803 Asp Gln Met Gln Gln Ala Pro Gly Gly Leu Ser Gln Met Gly Pro 1875 1880 1885 gtg tcc ctg ttc cac cct ctg aag gcc acc ctg gag cag aca cag 5848 Val Ser Leu Phe His Pro Leu Lys Ala Thr Leu Glu Gln Thr Gln 1890 1895 1900 ccg gct gtg ctc cga gga gcc cgg gtt ttc ctt cga cag aag agt 5893 Pro Ala Val Leu Arg Gly Ala Arg Val Phe Leu Arg Gln Lys Ser 1905 1910 1915 tcc acc tcc ctc agc aat ggc ggg gcc ata caa aac caa gag agt 5938 Ser Thr Ser Leu Ser Asn Gly Gly Ala Ile Gln Asn Gln Glu Ser 1920 1925 1930 ggc atc aaa gag tct gtc tcc tgg ggc act caa agg acc cag gat 5983 Gly Ile Lys Glu Ser Val Ser Trp Gly Thr Gln Arg Thr Gln Asp 1935 1940 1945 gca ccc cat gag gcc agg cca ccc ctg gag cgt ggc cac tcc aca 6028 Ala Pro His Glu Ala Arg Pro Pro Leu Glu Arg Gly His Ser Thr 1950 1955 1960 gag atc cct gtg ggg cgg tca gga gca ctg gct gtg gac gtt cag 6073 Glu Ile Pro Val Gly Arg Ser Gly Ala Leu Ala Val Asp Val Gln 1965 1970 1975 atg cag agc ata acc cgg agg ggc cct gat ggg gag ccc cag cct 6118 Met Gln Ser Ile Thr Arg Arg Gly Pro Asp Gly Glu Pro Gln Pro 1980 1985 1990 ggg ctg gag agc cag ggt cga gcg gcc tcc atg ccc cgc ctt gcg 6163 Gly Leu Glu Ser Gln Gly Arg Ala Ala Ser Met Pro Arg Leu Ala 1995 2000 2005 gcc gag act cag ccc gtc aca gat gcc agc ccc atg aag cgc tcc 6208 Ala Glu Thr Gln Pro Val Thr Asp Ala Ser Pro Met Lys Arg Ser 2010 2015 2020 atc tcc acg ctg gcc cag cgg ccc cgt ggg act cat ctt tgc agc 6253 Ile Ser Thr Leu Ala Gln Arg Pro Arg Gly Thr His Leu Cys Ser 2025 2030 2035 acc acc ccg gac cgc cca ccc cct agc cag gcg tcg tcg cac cac 6298 Thr Thr Pro Asp Arg Pro Pro Pro Ser Gln Ala Ser Ser His His 2040 2045 2050 cac cac cac cgc tgc cac cgc cgc agg gac agg aag cag agg tcc 6343 His His His Arg Cys His Arg Arg Arg Asp Arg Lys Gln Arg Ser 2055 2060 2065 ctg gag aag ggg ccc agc ctg tct gcc gat atg gat ggc gca cca 6388 Leu Glu Lys Gly Pro Ser Leu Ser Ala Asp Met Asp Gly Ala Pro 2070 2075 2080 agc agt gct gtg ggg ccg ggg ctg ccc ccg gga gag ggg cct aca 6433 Ser Ser Ala Val Gly Pro Gly Leu Pro Pro Gly Glu Gly Pro Thr 2085 2090 2095 ggc tgc cgg cgg gaa cga gag cgc cgg cag gag cgg ggc cgg tcc 6478 Gly Cys Arg Arg Glu Arg Glu Arg Arg Gln Glu Arg Gly Arg Ser 2100 2105 2110 cag gag cgg agg cag ccc tca tcc tcc tcc tcg gag aag cag cgc 6523 Gln Glu Arg Arg Gln Pro Ser Ser Ser Ser Ser Glu Lys Gln Arg 2115 2120 2125 ttc tac tcc tgc gac cgc ttt ggg ggc cgt gag ccc ccg aag ccc 6568 Phe Tyr Ser Cys Asp Arg Phe Gly Gly Arg Glu Pro Pro Lys Pro 2130 2135 2140 aag ccc tcc ctc agc agc cac cca acg tcg cca aca gct ggc cag 6613 Lys Pro Ser Leu Ser Ser His Pro Thr Ser Pro Thr Ala Gly Gln 2145 2150 2155 gag ccg gga ccc cac cca cag ggc agt ggt tcc gtg aat ggg agc 6658 Glu Pro Gly Pro His Pro Gln Gly Ser Gly Ser Val Asn Gly Ser 2160 2165 2170 ccc ttg ctg tca aca tct ggt gct agc acc ccc ggc cgc ggt ggg 6703 Pro Leu Leu Ser Thr Ser Gly Ala Ser Thr Pro Gly Arg Gly Gly 2175 2180 2185 cgg agg cag ctc ccc cag acg ccc ctg act ccc cgc ccc agc atc 6748 Arg Arg Gln Leu Pro Gln Thr Pro Leu Thr Pro Arg Pro Ser Ile 2190 2195 2200 acc tac aag acg gcc aac tcc tca ccc atc cac ttc gcc ggg gct 6793 Thr Tyr Lys Thr Ala Asn Ser Ser Pro Ile His Phe Ala Gly Ala 2205 2210 2215 cag acc agc ctc cct gcc ttc tcc cca ggc cgg ctc agc cgt ggg 6838 Gln Thr Ser Leu Pro Ala Phe Ser Pro Gly Arg Leu Ser Arg Gly 2220 2225 2230 ctt tcc gaa cac aac gcc ctg ctg cag aga gac ccc ctc agc cag 6883 Leu Ser Glu His Asn Ala Leu Leu Gln Arg Asp Pro Leu Ser Gln 2235 2240 2245 ccc ctg gcc cct ggc tct cga att ggc tct gac cct tac ctg ggg 6928 Pro Leu Ala Pro Gly Ser Arg Ile Gly Ser Asp Pro Tyr Leu Gly 2250 2255 2260 cag cgt ctg gac agt gag gcc tct gtc cac gcc ctg cct gag gac 6973 Gln Arg Leu Asp Ser Glu Ala Ser Val His Ala Leu Pro Glu Asp 2265 2270 2275 acg ctc act ttc gag gag gct gtg gcc acc aac tcg ggc cgc tcc 7018 Thr Leu Thr Phe Glu Glu Ala Val Ala Thr Asn Ser Gly Arg Ser 2280 2285 2290 tcc agg act tcc tac gtg tcc tcc ctg acc tcc cag tct cac cct 7063 Ser Arg Thr Ser Tyr Val Ser Ser Leu Thr Ser Gln Ser His Pro 2295 2300 2305 ctc cgc cgc gtg ccc aac ggt tac cac tgc acc ctg gga ctc agc 7108 Leu Arg Arg Val Pro Asn Gly Tyr His Cys Thr Leu Gly Leu Ser 2310 2315 2320 tcg ggt ggc cga gca cgg cac agc tac cac cac cct gac caa gac 7153 Ser Gly Gly Arg Ala Arg His Ser Tyr His His Pro Asp Gln Asp 2325 2330 2335 cac tgg tgc tag ctgcaccgtg accgctcaga cgcctgcatg cagcaggcgt 7205 His Trp Cys gtgttccagt ggatgagttt tatcatccac acggggcagt cggccctcgg gggaggcctt 7265 gcccaccttg gtgaggctcc tgtggcccct ccctccccct cctcccctct tttactctag 7325 acgacgaata aagccctgtt gcttgagtgt acgtaccgc 7364 32 2339 PRT Homo sapiens 32 Met Val Arg Phe Gly Asp Glu Leu Gly Gly Arg Tyr Gly Gly Pro Gly 1 5 10 15 Gly Gly Glu Arg Ala Arg Gly Gly Gly Ala Gly Gly Ala Gly Gly Pro 20 25 30 Gly Pro Gly Gly Leu Gln Pro Gly Gln Arg Val Leu Tyr Lys Gln Ser 35 40 45 Ile Ala Gln Arg Ala Arg Thr Met Ala Leu Tyr Asn Pro Ile Pro Val 50 55 60 Lys Gln Asn Cys Phe Thr Val Asn Arg Ser Leu Phe Val Phe Ser Glu 65 70 75 80 Asp Asn Val Val Arg Lys Tyr Ala Lys Arg Ile Thr Glu Trp Pro Pro 85 90 95 Phe Glu Tyr Met Ile Leu Ala Thr Ile Ile Ala Asn Cys Ile Val Leu 100 105 110 Ala Leu Glu Gln His Leu Pro Asp Gly Asp Lys Thr Pro Met Ser Glu 115 120 125 Arg Leu Asp Asp Thr Glu Pro Tyr Phe Ile Gly Ile Phe Cys Phe Glu 130 135 140 Ala Gly Ile Lys Ile Ile Ala Leu Gly Phe Val Phe His Lys Gly Ser 145 150 155 160 Tyr Leu Arg Asn Gly Trp Asn Val Met Asp Phe Val Val Val Leu Thr 165 170 175 Gly Ile Leu Ala Thr Ala Gly Thr Asp Phe Asp Leu Arg Thr Leu Arg 180 185 190 Ala Val Arg Val Leu Arg Pro Leu Lys Leu Val Ser Gly Ile Pro Ser 195 200 205 Leu Gln Val Val Leu Lys Ser Ile Met Lys Ala Met Val Pro Leu Leu 210 215 220 Gln Ile Gly Leu Leu Leu Phe Phe Ala Ile Leu Met Phe Ala Ile Ile 225 230 235 240 Gly Leu Glu Phe Tyr Met Gly Lys Phe His Lys Ala Cys Phe Pro Asn 245 250 255 Ser Thr Asp Ala Glu Pro Val Gly Asp Phe Pro Cys Gly Lys Glu Ala 260 265 270 Pro Ala Arg Leu Cys Glu Gly Asp Thr Glu Cys Arg Glu Tyr Trp Pro 275 280 285 Gly Pro Asn Phe Gly Ile Thr Asn Phe Asp Asn Ile Leu Phe Ala Ile 290 295 300 Leu Thr Val Phe Gln Cys Ile Thr Met Glu Gly Trp Thr Asp Ile Leu 305 310 315 320 Tyr Asn Thr Asn Asp Ala Ala Gly Asn Thr Trp Asn Trp Leu Tyr Phe 325 330 335 Ile Pro Leu Ile Ile Ile Gly Ser Phe Phe Met Leu Asn Leu Val Leu 340 345 350 Gly Val Leu Ser Gly Glu Phe Ala Lys Glu Arg Glu Arg Val Glu Asn 355 360 365 Arg Arg Ala Phe Leu Lys Leu Arg Arg Gln Gln Gln Ile Glu Arg Glu 370 375 380 Leu Asn Gly Tyr Leu Glu Trp Ile Phe Lys Ala Glu Glu Val Met Leu 385 390 395 400 Ala Glu Glu Asp Arg Asn Ala Glu Glu Lys Ser Pro Leu Asp Val Leu 405 410 415 Lys Arg Ala Ala Thr Lys Lys Ser Arg Asn Asp Leu Ile His Ala Glu 420 425 430 Glu Gly Glu Asp Arg Phe Ala Asp Leu Cys Ala Val Gly Ser Pro Phe 435 440 445 Ala Arg Ala Ser Leu Lys Ser Gly Lys Thr Glu Ser Ser Ser Tyr Phe 450 455 460 Arg Arg Lys Glu Lys Met Phe Arg Phe Phe Ile Arg Arg Met Val Lys 465 470 475 480 Ala Gln Ser Phe Tyr Trp Val Val Leu Cys Val Val Ala Leu Asn Thr 485 490 495 Leu Cys Val Ala Met Val His Tyr Asn Gln Pro Arg Arg Leu Thr Thr 500 505 510 Thr Leu Tyr Phe Ala Glu Phe Val Phe Leu Gly Leu Phe Leu Thr Glu 515 520 525 Met Ser Leu Lys Met Tyr Gly Leu Gly Pro Arg Ser Tyr Phe Arg Ser 530 535 540 Ser Phe Asn Cys Phe Asp Phe Gly Val Ile Val Gly Ser Val Phe Glu 545 550 555 560 Val Val Trp Ala Ala Ile Lys Pro Gly Ser Ser Phe Gly Ile Ser Val 565 570 575 Leu Arg Ala Leu Arg Leu Leu Arg Ile Phe Lys Val Thr Lys Tyr Trp 580 585 590 Ser Ser Leu Arg Asn Leu Val Val Ser Leu Leu Asn Ser Met Lys Ser 595 600 605 Ile Ile Ser Leu Leu Phe Leu Leu Phe Leu Phe Ile Val Val Phe Ala 610 615 620 Leu Leu Gly Met Gln Leu Phe Gly Gly Gln Phe Asn Phe Gln Asp Glu 625 630 635 640 Thr Pro Thr Thr Asn Phe Asp Thr Phe Pro Ala Ala Ile Leu Thr Val 645 650 655 Phe Gln Ile Leu Thr Gly Glu Asp Trp Asn Ala Val Met Tyr His Gly 660 665 670 Ile Glu Ser Gln Gly Gly Val Ser Lys Gly Met Phe Ser Ser Phe Tyr 675 680 685 Phe Ile Val Leu Thr Leu Phe Gly Asn Tyr Thr Leu Leu Asn Val Phe 690 695 700 Leu Ala Ile Ala Val Asp Asn Leu Ala Asn Ala Gln Glu Leu Thr Lys 705 710 715 720 Asp Glu Glu Glu Met Glu Glu Ala Ala Asn Gln Lys Leu Ala Leu Gln 725 730 735 Lys Ala Lys Glu Val Ala Glu Val Ser Pro Met Ser Ala Ala Asn Ile 740 745 750 Ser Ile Ala Ala Arg Gln Gln Asn Ser Ala Lys Ala Arg Ser Val Trp 755 760 765 Glu Gln Arg Ala Ser Gln Leu Arg Leu Gln Asn Leu Arg Ala Ser Cys 770 775 780 Glu Ala Leu Tyr Ser Glu Met Asp Pro Glu Glu Arg Leu Arg Phe Ala 785 790 795 800 Thr Thr Arg His Leu Arg Pro Asp Met Lys Thr His Leu Asp Arg Pro 805 810 815 Leu Val Val Glu Leu Gly Arg Asp Gly Ala Arg Gly Pro Val Gly Gly 820 825 830 Lys Ala Arg Pro Glu Ala Ala Glu Ala Pro Glu Gly Val Asp Pro Pro 835 840 845 Arg Arg His His Arg His Arg Asp Lys Asp Lys Thr Pro Ala Ala Gly 850 855 860 Asp Gln Asp Arg Ala Glu Ala Pro Lys Ala Glu Ser Gly Glu Pro Gly 865 870 875 880 Ala Arg Glu Glu Arg Pro Arg Pro His Arg Ser His Ser Lys Glu Ala 885 890 895 Ala Gly Pro Pro Glu Ala Arg Ser Glu Arg Gly Arg Gly Pro Gly Pro 900 905 910 Glu Gly Gly Arg Arg His His Arg Arg Gly Ser Pro Glu Glu Ala Ala 915 920 925 Glu Arg Glu Pro Arg Arg His Arg Ala His Arg His Gln Asp Pro Ser 930 935 940 Lys Glu Cys Ala Gly Ala Lys Gly Glu Arg Arg Ala Arg His Arg Gly 945 950 955 960 Gly Pro Arg Ala Gly Pro Arg Glu Ala Glu Ser Gly Glu Glu Pro Ala 965 970 975 Arg Arg His Arg Ala Arg His Lys Ala Gln Pro Ala His Glu Ala Val 980 985 990 Glu Lys Glu Thr Thr Glu Lys Glu Ala Thr Glu Lys Glu Ala Glu Ile 995 1000 1005 Val Glu Ala Asp Lys Glu Lys Glu Leu Arg Asn His Gln Pro Arg 1010 1015 1020 Glu Pro His Cys Asp Leu Glu Thr Ser Gly Thr Val Thr Val Gly 1025 1030 1035 Pro Met His Thr Leu Pro Ser Thr Cys Leu Gln Lys Val Glu Glu 1040 1045 1050 Gln Pro Glu Asp Ala Asp Asn Gln Arg Asn Val Thr Arg Met Gly 1055 1060 1065 Ser Gln Pro Pro Asp Pro Asn Thr Ile Val His Ile Pro Val Met 1070 1075 1080 Leu Thr Gly Pro Leu Gly Glu Ala Thr Val Val Pro Ser Gly Asn 1085 1090 1095 Val Asp Leu Glu Ser Gln Ala Glu Gly Lys Lys Glu Val Glu Ala 1100 1105 1110 Asp Asp Val Met Arg Ser Gly Pro Arg Pro Ile Val Pro Tyr Ser 1115 1120 1125 Ser Met Phe Cys Leu Ser Pro Thr Asn Leu Leu Arg Arg Phe Cys 1130 1135 1140 His Tyr Ile Val Thr Met Arg Tyr Phe Glu Val Val Ile Leu Val 1145 1150 1155 Val Ile Ala Leu Ser Ser Ile Ala Leu Ala Ala Glu Asp Pro Val 1160 1165 1170 Arg Thr Asp Ser Pro Arg Asn Asn Ala Leu Lys Tyr Leu Asp Tyr 1175 1180 1185 Ile Phe Thr Gly Val Phe Thr Phe Glu Met Val Ile Lys Met Ile 1190 1195 1200 Asp Leu Gly Leu Leu Leu His Pro Gly Ala Tyr Phe Arg Asp Leu 1205 1210 1215 Trp Asn Ile Leu Asp Phe Ile Val Val Ser Gly Ala Leu Val Ala 1220 1225 1230 Phe Ala Phe Ser Gly Ser Lys Gly Lys Asp Ile Asn Thr Ile Lys 1235 1240 1245 Ser Leu Arg Val Leu Arg Val Leu Arg Pro Leu Lys Thr Ile Lys 1250 1255 1260 Arg Leu Pro Lys Leu Lys Ala Val Phe Asp Cys Val Val Asn Ser 1265 1270 1275 Leu Lys Asn Val Leu Asn Ile Leu Ile Val Tyr Met Leu Phe Met 1280 1285 1290 Phe Ile Phe Ala Val Ile Ala Val Gln Leu Phe Lys Gly Lys Phe 1295 1300 1305 Phe Tyr Cys Thr Asp Glu Ser Lys Glu Leu Glu Arg Asp Cys Arg 1310 1315 1320 Gly Gln Tyr Leu Asp Tyr Glu Lys Glu Glu Val Glu Ala Gln Pro 1325 1330 1335 Arg Gln Trp Lys Lys Tyr Asp Phe His Tyr Asp Asn Val Leu Trp 1340 1345 1350 Ala Leu Leu Thr Leu Phe Thr Val Ser Thr Gly Glu Gly Trp Pro 1355 1360 1365 Met Val Leu Lys His Ser Val Asp Ala Thr Tyr Glu Glu Gln Gly 1370 1375 1380 Pro Ser Pro Gly Tyr Arg Met Glu Leu Ser Ile Phe Tyr Val Val 1385 1390 1395 Tyr Phe Val Val Phe Pro Phe Phe Phe Val Asn Ile Phe Val Ala 1400 1405 1410 Leu Ile Ile Ile Thr Phe Gln Glu Gln Gly Asp Lys Val Met Ser 1415 1420 1425 Glu Cys Ser Leu Glu Lys Asn Glu Arg Ala Cys Ile Asp Phe Ala 1430 1435 1440 Ile Ser Ala Lys Pro Leu Thr Arg Tyr Met Pro Gln Asn Arg Gln 1445 1450 1455 Ser Phe Gln Tyr Lys Thr Trp Thr Phe Val Val Ser Pro Pro Phe 1460 1465 1470 Glu Tyr Phe Ile Met Ala Met Ile Ala Leu Asn Thr Val Val Leu 1475 1480 1485 Met Met Lys Phe Tyr Asp Ala Pro Tyr Glu Tyr Glu Leu Met Leu 1490 1495 1500 Lys Cys Leu Asn Ile Val Phe Thr Ser Met Phe Ser Met Glu Cys 1505 1510 1515 Val Leu Lys Ile Ile Ala Phe Gly Val Leu Asn Tyr Phe Arg Asp 1520 1525 1530 Ala Trp Asn Val Phe Asp Phe Val Thr Val Leu Gly Ser Ile Thr 1535 1540 1545 Asp Ile Leu Val Thr Glu Ile Ala Glu Thr Asn Asn Phe Ile Asn 1550 1555 1560 Leu Ser Phe Leu Arg Leu Phe Arg Ala Ala Arg Leu Ile Lys Leu 1565 1570 1575 Leu Arg Gln Gly Tyr Thr Ile Arg Ile Leu Leu Trp Thr Phe Val 1580 1585 1590 Gln Ser Phe Lys Ala Leu Pro Tyr Val Cys Leu Leu Ile Ala Met 1595 1600 1605 Leu Phe Phe Ile Tyr Ala Ile Ile Gly Met Gln Val Phe Gly Asn 1610 1615 1620 Ile Ala Leu Asp Asp Asp Thr Ser Ile Asn Arg His Asn Asn Phe 1625 1630 1635 Arg Thr Phe Leu Gln Ala Leu Met Leu Leu Phe Arg Ser Ala Thr 1640 1645 1650 Gly Glu Ala Trp His Glu Ile Met Leu Ser Cys Leu Ser Asn Gln 1655 1660 1665 Ala Cys Asp Glu Gln Ala Asn Ala Thr Glu Cys Gly Ser Asp Phe 1670 1675 1680 Ala Tyr Phe Tyr Phe Val Ser Phe Ile Phe Leu Cys Ser Phe Leu 1685 1690 1695 Met Leu Asn Leu Phe Val Ala Val Ile Met Asp Asn Phe Glu Tyr 1700 1705 1710 Leu Thr Arg Asp Ser Ser Ile Leu Gly Pro His His Leu Asp Glu 1715 1720 1725 Phe Ile Arg Val Trp Ala Glu Tyr Asp Pro Ala Ala Cys Gly Arg 1730 1735 1740 Ile Ser Tyr Asn Asp Met Phe Glu Met Leu Lys His Met Ser Pro 1745 1750 1755 Pro Leu Gly Leu Gly Lys Lys Cys Pro Ala Arg Val Ala Tyr Lys 1760 1765 1770 Arg Leu Val Arg Met Asn Met Pro Ile Ser Asn Glu Asp Met Thr 1775 1780 1785 Val His Phe Thr Ser Thr Leu Met Ala Leu Ile Arg Thr Ala Leu 1790 1795 1800 Glu Ile Lys Leu Ala Pro Ala Gly Thr Lys Gln His Gln Cys Asp 1805 1810 1815 Ala Glu Leu Arg Lys Glu Ile Ser Val Val Trp Ala Asn Leu Pro 1820 1825 1830 Gln Lys Thr Leu Asp Leu Leu Val Pro Pro His Lys Pro Asp Glu 1835 1840 1845 Met Thr Val Gly Lys Val Tyr Ala Ala Leu Met Ile Phe Asp Phe 1850 1855 1860 Tyr Lys Gln Asn Lys Thr Thr Arg Asp Gln Met Gln Gln Ala Pro 1865 1870 1875 Gly Gly Leu Ser Gln Met Gly Pro Val Ser Leu Phe His Pro Leu 1880 1885 1890 Lys Ala Thr Leu Glu Gln Thr Gln Pro Ala Val Leu Arg Gly Ala 1895 1900 1905 Arg Val Phe Leu Arg Gln Lys Ser Ser Thr Ser Leu Ser Asn Gly 1910 1915 1920 Gly Ala Ile Gln Asn Gln Glu Ser Gly Ile Lys Glu Ser Val Ser 1925 1930 1935 Trp Gly Thr Gln Arg Thr Gln Asp Ala Pro His Glu Ala Arg Pro 1940 1945 1950 Pro Leu Glu Arg Gly His Ser Thr Glu Ile Pro Val Gly Arg Ser 1955 1960 1965 Gly Ala Leu Ala Val Asp Val Gln Met Gln Ser Ile Thr Arg Arg 1970 1975 1980 Gly Pro Asp Gly Glu Pro Gln Pro Gly Leu Glu Ser Gln Gly Arg 1985 1990 1995 Ala Ala Ser Met Pro Arg Leu Ala Ala Glu Thr Gln Pro Val Thr 2000 2005 2010 Asp Ala Ser Pro Met Lys Arg Ser Ile Ser Thr Leu Ala Gln Arg 2015 2020 2025 Pro Arg Gly Thr His Leu Cys Ser Thr Thr Pro Asp Arg Pro Pro 2030 2035 2040 Pro Ser Gln Ala Ser Ser His His His His His Arg Cys His Arg 2045 2050 2055 Arg Arg Asp Arg Lys Gln Arg Ser Leu Glu Lys Gly Pro Ser Leu 2060 2065 2070 Ser Ala Asp Met Asp Gly Ala Pro Ser Ser Ala Val Gly Pro Gly 2075 2080 2085 Leu Pro Pro Gly Glu Gly Pro Thr Gly Cys Arg Arg Glu Arg Glu 2090 2095 2100 Arg Arg Gln Glu Arg Gly Arg Ser Gln Glu Arg Arg Gln Pro Ser 2105 2110 2115 Ser Ser Ser Ser Glu Lys Gln Arg Phe Tyr Ser Cys Asp Arg Phe 2120 2125 2130 Gly Gly Arg Glu Pro Pro Lys Pro Lys Pro Ser Leu Ser Ser His 2135 2140 2145 Pro Thr Ser Pro Thr Ala Gly Gln Glu Pro Gly Pro His Pro Gln 2150 2155 2160 Gly Ser Gly Ser Val Asn Gly Ser Pro Leu Leu Ser Thr Ser Gly 2165 2170 2175 Ala Ser Thr Pro Gly Arg Gly Gly Arg Arg Gln Leu Pro Gln Thr 2180 2185 2190 Pro Leu Thr Pro Arg Pro Ser Ile Thr Tyr Lys Thr Ala Asn Ser 2195 2200 2205 Ser Pro Ile His Phe Ala Gly Ala Gln Thr Ser Leu Pro Ala Phe 2210 2215 2220 Ser Pro Gly Arg Leu Ser Arg Gly Leu Ser Glu His Asn Ala Leu 2225 2230 2235 Leu Gln Arg Asp Pro Leu Ser Gln Pro Leu Ala Pro Gly Ser Arg 2240 2245 2250 Ile Gly Ser Asp Pro Tyr Leu Gly Gln Arg Leu Asp Ser Glu Ala 2255 2260 2265 Ser Val His Ala Leu Pro Glu Asp Thr Leu Thr Phe Glu Glu Ala 2270 2275 2280 Val Ala Thr Asn Ser Gly Arg Ser Ser Arg Thr Ser Tyr Val Ser 2285 2290 2295 Ser Leu Thr Ser Gln Ser His Pro Leu Arg Arg Val Pro Asn Gly 2300 2305 2310 Tyr His Cys Thr Leu Gly Leu Ser Ser Gly Gly Arg Ala Arg His 2315 2320 2325 Ser Tyr His His Pro Asp Gln Asp His Trp Cys 2330 2335 33 7177 DNA Homo sapiens CDS (146)..(6859) 33 gcggcggcgg ctgcggcggt ggggccgggc gaggtccgct gcggtcccgg cggctccgtg 60 gctgctccgc tctgagcgcc tggcgcgccc cgcgccctcc ctgccggggc cgctgggccg 120 gggatgcacg cggggcccgg gagcc atg gtc cgc ttc ggg gac gag ctg ggc 172 Met Val Arg Phe Gly Asp Glu Leu Gly 1 5 ggc cgc tat gga ggc ccc ggc ggc gga gag cgg gcc cgg ggc ggc ggg 220 Gly Arg Tyr Gly Gly Pro Gly Gly Gly Glu Arg Ala Arg Gly Gly Gly 10 15 20 25 gcc ggc ggg gcg ggg ggc ccg ggt ccc ggg ggg ctg cag ccc ggc cag 268 Ala Gly Gly Ala Gly Gly Pro Gly Pro Gly Gly Leu Gln Pro Gly Gln 30 35 40 cgg gtc ctc tac aag caa tcg atc gcg cag cgc gcg cgg acc atg gcg 316 Arg Val Leu Tyr Lys Gln Ser Ile Ala Gln Arg Ala Arg Thr Met Ala 45 50 55 ctg tac aac ccc atc ccg gtc aag cag aac tgc ttc acc gtc aac cgc 364 Leu Tyr Asn Pro Ile Pro Val Lys Gln Asn Cys Phe Thr Val Asn Arg 60 65 70 tcg ctc ttc gtc ttc agc gag gac aac gtc gtc cgc aaa tac gcg aag 412 Ser Leu Phe Val Phe Ser Glu Asp Asn Val Val Arg Lys Tyr Ala Lys 75 80 85 cgc atc acc gag tgg cct cca ttc gag tat atg atc ctg gcc acc atc 460 Arg Ile Thr Glu Trp Pro Pro Phe Glu Tyr Met Ile Leu Ala Thr Ile 90 95 100 105 atc gcc aac tgc atc gtg ctg gcc ctg gag cag cac ctc cct gat ggg 508 Ile Ala Asn Cys Ile Val Leu Ala Leu Glu Gln His Leu Pro Asp Gly 110 115 120 gac aaa acg ccc atg tcc gag cgg ctg gac gac acg gag ccc tat ttc 556 Asp Lys Thr Pro Met Ser Glu Arg Leu Asp Asp Thr Glu Pro Tyr Phe 125 130 135 atc ggg atc ttt tgc ttc gag gca ggg atc aaa atc atc gct ctg ggc 604 Ile Gly Ile Phe Cys Phe Glu Ala Gly Ile Lys Ile Ile Ala Leu Gly 140 145 150 ttt gtc ttc cac aag ggc tct tac ctg cgg aac ggc tgg aac gtc atg 652 Phe Val Phe His Lys Gly Ser Tyr Leu Arg Asn Gly Trp Asn Val Met 155 160 165 gac ttc gtg gtc gtc ctc aca ggg atc ctt gcc acg gct gga act gac 700 Asp Phe Val Val Val Leu Thr Gly Ile Leu Ala Thr Ala Gly Thr Asp 170 175 180 185 ttc gac ctg cga aca ctg agg gct gtg cgt gtg ctg agg ccc ctg aag 748 Phe Asp Leu Arg Thr Leu Arg Ala Val Arg Val Leu Arg Pro Leu Lys 190 195 200 ctg gtg tct ggg att cca agt ttg cag gtg gtg ctc aag tcc atc atg 796 Leu Val Ser Gly Ile Pro Ser Leu Gln Val Val Leu Lys Ser Ile Met 205 210 215 aag gcc atg gtt cca ctc ctg cag att ggg ctg ctt ctc ttc ttt gcc 844 Lys Ala Met Val Pro Leu Leu Gln Ile Gly Leu Leu Leu Phe Phe Ala 220 225 230 atc ctc atg ttt gcc atc att ggc ctg gag ttc tac atg ggc aag ttc 892 Ile Leu Met Phe Ala Ile Ile Gly Leu Glu Phe Tyr Met Gly Lys Phe 235 240 245 cac aag gcc tgt ttc ccc aac agc aca gat gcg gag ccc gtg ggt gac 940 His Lys Ala Cys Phe Pro Asn Ser Thr Asp Ala Glu Pro Val Gly Asp 250 255 260 265 ttc ccc tgt ggc aag gag gcc cca gcc cgg ctg tgc gag ggc gac act 988 Phe Pro Cys Gly Lys Glu Ala Pro Ala Arg Leu Cys Glu Gly Asp Thr 270 275 280 gag tgc cgg gag tac tgg cca gga ccc aac ttt ggc atc acc aac ttt 1036 Glu Cys Arg Glu Tyr Trp Pro Gly Pro Asn Phe Gly Ile Thr Asn Phe 285 290 295 gac aat atc ctg ttt gcc atc ttg acg gtg ttc cag tgc atc acc atg 1084 Asp Asn Ile Leu Phe Ala Ile Leu Thr Val Phe Gln Cys Ile Thr Met 300 305 310 gag ggc tgg act gac atc ctc tat aat aca aac gat gcg gcc ggc aac 1132 Glu Gly Trp Thr Asp Ile Leu Tyr Asn Thr Asn Asp Ala Ala Gly Asn 315 320 325 acc tgg aac tgg ctc tac ttc atc cct ctc atc atc atc ggc tcc ttc 1180 Thr Trp Asn Trp Leu Tyr Phe Ile Pro Leu Ile Ile Ile Gly Ser Phe 330 335 340 345 ttc atg ctc aac ctg gtg ctg ggc gtg ctc tcg ggg gag ttt gcc aag 1228 Phe Met Leu Asn Leu Val Leu Gly Val Leu Ser Gly Glu Phe Ala Lys 350 355 360 gag cga gag agg gtg gag aac cgc cgc gcc ttc ctg aag ctg cgc cgg 1276 Glu Arg Glu Arg Val Glu Asn Arg Arg Ala Phe Leu Lys Leu Arg Arg 365 370 375 cag cag cag atc gag cga gag ctc aac ggg tac ctg gag tgg atc ttc 1324 Gln Gln Gln Ile Glu Arg Glu Leu Asn Gly Tyr Leu Glu Trp Ile Phe 380 385 390 aag gcg gag gaa gtc atg ctg gcc gag gag gac agg aat gca gag gag 1372 Lys Ala Glu Glu Val Met Leu Ala Glu Glu Asp Arg Asn Ala Glu Glu 395 400 405 aag tcc cct ttg gac gtg ctg aag aga gcg gcc acc aag aag agc aga 1420 Lys Ser Pro Leu Asp Val Leu Lys Arg Ala Ala Thr Lys Lys Ser Arg 410 415 420 425 aat gac ctg atc cac gca gag gag gga gag gac cgg ttt gca gat ctc 1468 Asn Asp Leu Ile His Ala Glu Glu Gly Glu Asp Arg Phe Ala Asp Leu 430 435 440 tgt gct gtt gga tcc ccc ttc gcc cgc gcc agc ctc aag agc ggg aag 1516 Cys Ala Val Gly Ser Pro Phe Ala Arg Ala Ser Leu Lys Ser Gly Lys 445 450 455 aca gag agc tcg tca tac ttc cgg agg aag gag aag atg ttc cgg ttt 1564 Thr Glu Ser Ser Ser Tyr Phe Arg Arg Lys Glu Lys Met Phe Arg Phe 460 465 470 ttt atc cgg cgc atg gtg aag gct cag agc ttc tac tgg gtg gtg ctg 1612 Phe Ile Arg Arg Met Val Lys Ala Gln Ser Phe Tyr Trp Val Val Leu 475 480 485 tgc gtg gtg gcc ctg aac aca ctg tgt gtg gcc atg gtg cat tac aac 1660 Cys Val Val Ala Leu Asn Thr Leu Cys Val Ala Met Val His Tyr Asn 490 495 500 505 cag ccg cgg cgg ctt acc acg acc ctg tat ttt gca gag ttt gtt ttc 1708 Gln Pro Arg Arg Leu Thr Thr Thr Leu Tyr Phe Ala Glu Phe Val Phe 510 515 520 ctg ggt ctc ttc ctc aca gag atg tcc ctg aag atg tat ggc ctg ggg 1756 Leu Gly Leu Phe Leu Thr Glu Met Ser Leu Lys Met Tyr Gly Leu Gly 525 530 535 ccc aga agc tac ttc cgg tcc tcc ttc aac tgc ttc gac ttt ggg gtc 1804 Pro Arg Ser Tyr Phe Arg Ser Ser Phe Asn Cys Phe Asp Phe Gly Val 540 545 550 atc gtg ggg agc gtc ttt gaa gtg gtc tgg gcg gcc atc aag ccg gga 1852 Ile Val Gly Ser Val Phe Glu Val Val Trp Ala Ala Ile Lys Pro Gly 555 560 565 agc tcc ttt ggg atc agt gtg ctg cgg gcc ctc cgc ctg ctg agg atc 1900 Ser Ser Phe Gly Ile Ser Val Leu Arg Ala Leu Arg Leu Leu Arg Ile 570 575 580 585 ttc aaa gtc acg aag tac tgg agc tcc ctg cgg aac ctg gtg gtg tcc 1948 Phe Lys Val Thr Lys Tyr Trp Ser Ser Leu Arg Asn Leu Val Val Ser 590 595 600 ctg ctg aac tcc atg aag tcc atc atc agc ctg ctc ttc ttg ctc ttc 1996 Leu Leu Asn Ser Met Lys Ser Ile Ile Ser Leu Leu Phe Leu Leu Phe 605 610 615 ctg ttc att gtg gtc ttc gcc ctg ctg ggg atg cag ctg ttt ggg gga 2044 Leu Phe Ile Val Val Phe Ala Leu Leu Gly Met Gln Leu Phe Gly Gly 620 625 630 cag ttc aac ttc cag gat gag act ccc aca acc aac ttc gac acc ttc 2092 Gln Phe Asn Phe Gln Asp Glu Thr Pro Thr Thr Asn Phe Asp Thr Phe 635 640 645 cct gcc gcc atc ctc act gtc ttc cag atc ctg acg gga gag gac tgg 2140 Pro Ala Ala Ile Leu Thr Val Phe Gln Ile Leu Thr Gly Glu Asp Trp 650 655 660 665 aat gca gtg atg tat cac ggg atc gaa tcg caa ggc ggc gtc agc aaa 2188 Asn Ala Val Met Tyr His Gly Ile Glu Ser Gln Gly Gly Val Ser Lys 670 675 680 ggc atg ttc tcg tcc ttt tac ttc att gtc ctg aca ctg ttc gga aac 2236 Gly Met Phe Ser Ser Phe Tyr Phe Ile Val Leu Thr Leu Phe Gly Asn 685 690 695 tac act ctg ctg aat gtc ttt ctg gcc atc gct gtg gac aac ctg gcc 2284 Tyr Thr Leu Leu Asn Val Phe Leu Ala Ile Ala Val Asp Asn Leu Ala 700 705 710 aac gcc caa gag ctg acc aag gat gaa gag gag atg gaa gaa gca gcc 2332 Asn Ala Gln Glu Leu Thr Lys Asp Glu Glu Glu Met Glu Glu Ala Ala 715 720 725 aat cag aag ctt gct ctg caa aag gcc aaa gaa gtg gct gaa gtc agc 2380 Asn Gln Lys Leu Ala Leu Gln Lys Ala Lys Glu Val Ala Glu Val Ser 730 735 740 745 ccc atg tct gcc gcg aac atc tcc atc gcc gcc agg cag cag aac tcg 2428 Pro Met Ser Ala Ala Asn Ile Ser Ile Ala Ala Arg Gln Gln Asn Ser 750 755 760 gcc aag gcg cgc tcg gtg tgg gag cag cgg gcc agc cag cta cgg ctg 2476 Ala Lys Ala Arg Ser Val Trp Glu Gln Arg Ala Ser Gln Leu Arg Leu 765 770 775 cag aac ctg cgg gcc agc tgc gag gcg ctg tac agc gag atg gac ccc 2524 Gln Asn Leu Arg Ala Ser Cys Glu Ala Leu Tyr Ser Glu Met Asp Pro 780 785 790 gag gag cgg ctg cgc ttc gcc act acg cgc cac ctg cgg ccc gac atg 2572 Glu Glu Arg Leu Arg Phe Ala Thr Thr Arg His Leu Arg Pro Asp Met 795 800 805 aag acg cac ctg gac cgg ccg ctg gtg gtg gag ctg ggc cgc gac ggc 2620 Lys Thr His Leu Asp Arg Pro Leu Val Val Glu Leu Gly Arg Asp Gly 810 815 820 825 gcg cgg ggg ccc gtg gga ggc aaa gcc cga cct gag gct gcg gag gcc 2668 Ala Arg Gly Pro Val Gly Gly Lys Ala Arg Pro Glu Ala Ala Glu Ala 830 835 840 ccc gag ggc gtc gac cct ccg cgc agg cac cac cgg cac cgc gac aag 2716 Pro Glu Gly Val Asp Pro Pro Arg Arg His His Arg His Arg Asp Lys 845 850 855 gac aag acc ccc gcg gcg ggg gac cag gac cga gca gag gcc ccg aag 2764 Asp Lys Thr Pro Ala Ala Gly Asp Gln Asp Arg Ala Glu Ala Pro Lys 860 865 870 gcg gag agc ggg gag ccc ggt gcc cgg gag gag cgg ccg cgg ccg cac 2812 Ala Glu Ser Gly Glu Pro Gly Ala Arg Glu Glu Arg Pro Arg Pro His 875 880 885 cgc agc cac agc aag gag gcc gcg ggg ccc ccg gag gcg cgg agc gag 2860 Arg Ser His Ser Lys Glu Ala Ala Gly Pro Pro Glu Ala Arg Ser Glu 890 895 900 905 cgc ggc cga ggc cca ggc ccc gag ggc ggc cgg cgg cac cac cgg cgc 2908 Arg Gly Arg Gly Pro Gly Pro Glu Gly Gly Arg Arg His His Arg Arg 910 915 920 ggc tcc ccg gag gag gcg gcc gag cgg gag ccc cga cgc cac cgc gcg 2956 Gly Ser Pro Glu Glu Ala Ala Glu Arg Glu Pro Arg Arg His Arg Ala 925 930 935 cac cgg cac cag gat ccg agc aag gag tgc gcc ggc gcc aag ggc gag 3004 His Arg His Gln Asp Pro Ser Lys Glu Cys Ala Gly Ala Lys Gly Glu 940 945 950 cgg cgc gcg cgg cac cgc ggc ggc ccc cga gcg ggg ccc cgg gag gcg 3052 Arg Arg Ala Arg His Arg Gly Gly Pro Arg Ala Gly Pro Arg Glu Ala 955 960 965 gag agc ggg gag gag ccg gcg cgg cgg cac cgg gcc cgg cac aag gcg 3100 Glu Ser Gly Glu Glu Pro Ala Arg Arg His Arg Ala Arg His Lys Ala 970 975 980 985 cag cct gct cac gag gct gtg gag aag gag acc acg gag aag gag gcc 3148 Gln Pro Ala His Glu Ala Val Glu Lys Glu Thr Thr Glu Lys Glu Ala 990 995 1000 acg gag aag gag gct gag ata gtg gaa gcc gac aag gaa aag gag 3193 Thr Glu Lys Glu Ala Glu Ile Val Glu Ala Asp Lys Glu Lys Glu 1005 1010 1015 ctc cgg aac cac cag ccc cgg gag cca cac tgt gac ctg gag acc 3238 Leu Arg Asn His Gln Pro Arg Glu Pro His Cys Asp Leu Glu Thr 1020 1025 1030 agt ggg act gtg act gtg ggt ccc atg cac aca ctg ccc agc acc 3283 Ser Gly Thr Val Thr Val Gly Pro Met His Thr Leu Pro Ser Thr 1035 1040 1045 tgt ctc cag aag gtg gag gaa cag cca gag gat gca gac aat cag 3328 Cys Leu Gln Lys Val Glu Glu Gln Pro Glu Asp Ala Asp Asn Gln 1050 1055 1060 cgg aac gtc act cgc atg ggc agt cag ccc cca gac ccg aac act 3373 Arg Asn Val Thr Arg Met Gly Ser Gln Pro Pro Asp Pro Asn Thr 1065 1070 1075 att gta cat atc cca gtg atg ctg acg ggc cct ctt ggg gaa gcc 3418 Ile Val His Ile Pro Val Met Leu Thr Gly Pro Leu Gly Glu Ala 1080 1085 1090 acg gtc gtt ccc agt ggt aac gtg gac ctg gaa agc caa gca gag 3463 Thr Val Val Pro Ser Gly Asn Val Asp Leu Glu Ser Gln Ala Glu 1095 1100 1105 ggg aag aag gag gtg gaa gcg gat gac gtg atg agg agc ggc ccc 3508 Gly Lys Lys Glu Val Glu Ala Asp Asp Val Met Arg Ser Gly Pro 1110 1115 1120 cgg cct atc gtc cca tac agc tcc atg ttc tgt tta agc ccc acc 3553 Arg Pro Ile Val Pro Tyr Ser Ser Met Phe Cys Leu Ser Pro Thr 1125 1130 1135 aac ctg ctc cgc cgc ttc tgc cac tac atc gtg acc atg agg tac 3598 Asn Leu Leu Arg Arg Phe Cys His Tyr Ile Val Thr Met Arg Tyr 1140 1145 1150 ttc gag gtg gtc att ctc gtg gtc atc gcc ttg agc agc atc gcc 3643 Phe Glu Val Val Ile Leu Val Val Ile Ala Leu Ser Ser Ile Ala 1155 1160 1165 ctg gct gct gag gac cca gtg cgc aca gac tcg ccc agg aac aac 3688 Leu Ala Ala Glu Asp Pro Val Arg Thr Asp Ser Pro Arg Asn Asn 1170 1175 1180 gct ctg aaa tac ctg gat tac att ttc act ggt gtc ttt acc ttt 3733 Ala Leu Lys Tyr Leu Asp Tyr Ile Phe Thr Gly Val Phe Thr Phe 1185 1190 1195 gag atg gtg ata aag atg atc gac ttg gga ctg ctg ctt cac cct 3778 Glu Met Val Ile Lys Met Ile Asp Leu Gly Leu Leu Leu His Pro 1200 1205 1210 gga gcc tat ttc cgg gac ttg tgg aac att ctg gac ttc att gtg 3823 Gly Ala Tyr Phe Arg Asp Leu Trp Asn Ile Leu Asp Phe Ile Val 1215 1220 1225 gtc agt ggc gcc ctg gtg gcg ttt gct ttc tca gga tcc aaa ggg 3868 Val Ser Gly Ala Leu Val Ala Phe Ala Phe Ser Gly Ser Lys Gly 1230 1235 1240 aaa gac atc aat acc atc aag tct ctg aga gtc ctt cgt gtc ctg 3913 Lys Asp Ile Asn Thr Ile Lys Ser Leu Arg Val Leu Arg Val Leu 1245 1250 1255 cgg ccc ctc aag acc atc aaa cgg ctg ccc aag ctc aag gct gtg 3958 Arg Pro Leu Lys Thr Ile Lys Arg Leu Pro Lys Leu Lys Ala Val 1260 1265 1270 ttt gac tgt gtg gtg aac tcc ctg aag aat gtc ctc aac atc ttg 4003 Phe Asp Cys Val Val Asn Ser Leu Lys Asn Val Leu Asn Ile Leu 1275 1280 1285 att gtc tac atg ctc ttc atg ttc ata ttt gcc gtc att gcg gtg 4048 Ile Val Tyr Met Leu Phe Met Phe Ile Phe Ala Val Ile Ala Val 1290 1295 1300 cag ctc ttc aaa ggg aag ttt ttc tac tgc aca gat gaa tcc aag 4093 Gln Leu Phe Lys Gly Lys Phe Phe Tyr Cys Thr Asp Glu Ser Lys 1305 1310 1315 gag ctg gag agg gac tgc agg ggt cag tat ttg gat tat gag aag 4138 Glu Leu Glu Arg Asp Cys Arg Gly Gln Tyr Leu Asp Tyr Glu Lys 1320 1325 1330 gag gaa gtg gaa gct cag ccc agg cag tgg aag aaa tac gac ttt 4183 Glu Glu Val Glu Ala Gln Pro Arg Gln Trp Lys Lys Tyr Asp Phe 1335 1340 1345 cac tac gac aat gtg ctc tgg gct ctg ctg acg ctg ttc aca gtg 4228 His Tyr Asp Asn Val Leu Trp Ala Leu Leu Thr Leu Phe Thr Val 1350 1355 1360 tcc acg gga gaa ggc tgg ccc atg gtg ctg aaa cac tcc gtg gat 4273 Ser Thr Gly Glu Gly Trp Pro Met Val Leu Lys His Ser Val Asp 1365 1370 1375 gcc acc tat gag gag cag ggt cca agc cct ggg tac cgc atg gag 4318 Ala Thr Tyr Glu Glu Gln Gly Pro Ser Pro Gly Tyr Arg Met Glu 1380 1385 1390 ctg tcc atc ttc tac gtg gtc tac ttt gtg gtc ttt ccc ttc ttc 4363 Leu Ser Ile Phe Tyr Val Val Tyr Phe Val Val Phe Pro Phe Phe 1395 1400 1405 ttc gtc aac atc ttt gtg gct ttg atc atc atc acc ttc cag gag 4408 Phe Val Asn Ile Phe Val Ala Leu Ile Ile Ile Thr Phe Gln Glu 1410 1415 1420 cag ggg gac aag gtg atg tct gaa tgc agc ctg gag aag aac gag 4453 Gln Gly Asp Lys Val Met Ser Glu Cys Ser Leu Glu Lys Asn Glu 1425 1430 1435 agg gct tgc att gac ttc gcc atc agc gcc aaa ccc ctg aca cgg 4498 Arg Ala Cys Ile Asp Phe Ala Ile Ser Ala Lys Pro Leu Thr Arg 1440 1445 1450 tac atg ccc caa aac cgg cag tcg ttc cag tat aag acg tgg aca 4543 Tyr Met Pro Gln Asn Arg Gln Ser Phe Gln Tyr Lys Thr Trp Thr 1455 1460 1465 ttt gtg gtc tcc ccg ccc ttt gaa tac ttc atc atg gcc atg ata 4588 Phe Val Val Ser Pro Pro Phe Glu Tyr Phe Ile Met Ala Met Ile 1470 1475 1480 gcc ctc aac act gtg gtg ctg atg atg aag ttc tat gat gca ccc 4633 Ala Leu Asn Thr Val Val Leu Met Met Lys Phe Tyr Asp Ala Pro 1485 1490 1495 tat gag tac gag ctg atg ctg aaa tgc ctg aac atc gtg ttc aca 4678 Tyr Glu Tyr Glu Leu Met Leu Lys Cys Leu Asn Ile Val Phe Thr 1500 1505 1510 tcc atg ttc tcc atg gaa tgc gtg ctg aag atc atc gcc ttt ggg 4723 Ser Met Phe Ser Met Glu Cys Val Leu Lys Ile Ile Ala Phe Gly 1515 1520 1525 gtg ctg aac tat ttc aga gat gcc tgg aat gtc ttt gac ttt gtc 4768 Val Leu Asn Tyr Phe Arg Asp Ala Trp Asn Val Phe Asp Phe Val 1530 1535 1540 act gtg ttg gga agt att act gat att tta gta aca gag att gcg 4813 Thr Val Leu Gly Ser Ile Thr Asp Ile Leu Val Thr Glu Ile Ala 1545 1550 1555 gaa acg aac aat ttc atc aac ctc agc ttc ctc cgc ctc ttt cga 4858 Glu Thr Asn Asn Phe Ile Asn Leu Ser Phe Leu Arg Leu Phe Arg 1560 1565 1570 gct gcg cgg ctg atc aag ctg ctc cgc cag ggc tac acc atc cgc 4903 Ala Ala Arg Leu Ile Lys Leu Leu Arg Gln Gly Tyr Thr Ile Arg 1575 1580 1585 atc ctg ctg tgg acc ttt gtc cag tcc ttc aag gcc ctg ccc tac 4948 Ile Leu Leu Trp Thr Phe Val Gln Ser Phe Lys Ala Leu Pro Tyr 1590 1595 1600 gtg tgt ctg ctc att gcc atg ctg ttc ttc atc tac gcc atc atc 4993 Val Cys Leu Leu Ile Ala Met Leu Phe Phe Ile Tyr Ala Ile Ile 1605 1610 1615 ggc atg cag gtg ttt ggg aat att gcc ctg gat gat gac acc agc 5038 Gly Met Gln Val Phe Gly Asn Ile Ala Leu Asp Asp Asp Thr Ser 1620 1625 1630 atc aac cgc cac aac aac ttc cgg acg ttt ttg caa gcc ctg atg 5083 Ile Asn Arg His Asn Asn Phe Arg Thr Phe Leu Gln Ala Leu Met 1635 1640 1645 ctg ctg ttc agg agc gcc acg ggg gag gcc tgg cac gag atc atg 5128 Leu Leu Phe Arg Ser Ala Thr Gly Glu Ala Trp His Glu Ile Met 1650 1655 1660 ctg tcc tgc ctg agc aac cag gcc tgt gat gag cag gcc aat gcc 5173 Leu Ser Cys Leu Ser Asn Gln Ala Cys Asp Glu Gln Ala Asn Ala 1665 1670 1675 acc gag tgt gga agt gac ttt gcc tac ttc tac ttc gtc tcc ttc 5218 Thr Glu Cys Gly Ser Asp Phe Ala Tyr Phe Tyr Phe Val Ser Phe 1680 1685 1690 atc ttc ctg tgc tcc ttt ctg atg ttg aac ctc ttt gtg gct gtg 5263 Ile Phe Leu Cys Ser Phe Leu Met Leu Asn Leu Phe Val Ala Val 1695 1700 1705 atc atg gac aat ttt gag tac ctc acg cgg gac tct tcc atc cta 5308 Ile Met Asp Asn Phe Glu Tyr Leu Thr Arg Asp Ser Ser Ile Leu 1710 1715 1720 ggt cct cac cac ttg gat gag ttc atc cgg gtc tgg gct gaa tac 5353 Gly Pro His His Leu Asp Glu Phe Ile Arg Val Trp Ala Glu Tyr 1725 1730 1735 gac ccg gct gcg tgt ggg cgc atc agt tac aat gac atg ttt gag 5398 Asp Pro Ala Ala Cys Gly Arg Ile Ser Tyr Asn Asp Met Phe Glu 1740 1745 1750 atg ctg aaa cac atg tcc ccg cct ctg ggg ctg ggg aag aaa tgc 5443 Met Leu Lys His Met Ser Pro Pro Leu Gly Leu Gly Lys Lys Cys 1755 1760 1765 cct gct cga gtt gct tac aag cgc ctg gtt cgc atg aac atg ccc 5488 Pro Ala Arg Val Ala Tyr Lys Arg Leu Val Arg Met Asn Met Pro 1770 1775 1780 atc tcc aac gag gac atg act gtt cac ttc acg tcc acg ctg atg 5533 Ile Ser Asn Glu Asp Met Thr Val His Phe Thr Ser Thr Leu Met 1785 1790 1795 gcc ctc atc cgg acg gca ctg gag atc aag ctg gcc cca gct ggg 5578 Ala Leu Ile Arg Thr Ala Leu Glu Ile Lys Leu Ala Pro Ala Gly 1800 1805 1810 aca aag cag cat cag tgt gac gcg gag ttg agg aag gag att tcc 5623 Thr Lys Gln His Gln Cys Asp Ala Glu Leu Arg Lys Glu Ile Ser 1815 1820 1825 gtt gtg tgg gcc aat ctg ccc cag aag act ttg gac ttg ctg gta 5668 Val Val Trp Ala Asn Leu Pro Gln Lys Thr Leu Asp Leu Leu Val 1830 1835 1840 cca ccc cat aag cct gat gag atg aca gtg ggg aag gtt tat gca 5713 Pro Pro His Lys Pro Asp Glu Met Thr Val Gly Lys Val Tyr Ala 1845 1850 1855 gct ctg atg ata ttt gac ttc tac aag cag aac aaa acc acc aga 5758 Ala Leu Met Ile Phe Asp Phe Tyr Lys Gln Asn Lys Thr Thr Arg 1860 1865 1870 gac cag atg cag cag gct cct gga ggc ctc tcc cag atg ggt cct 5803 Asp Gln Met Gln Gln Ala Pro Gly Gly Leu Ser Gln Met Gly Pro 1875 1880 1885 gtg tcc ctg ttc cac cct ctg aag gcc acc ctg gag cag aca cag 5848 Val Ser Leu Phe His Pro Leu Lys Ala Thr Leu Glu Gln Thr Gln 1890 1895 1900 ccg gct gtg ctc cga gga gcc cgg gtt ttc ctt cga cag aag agt 5893 Pro Ala Val Leu Arg Gly Ala Arg Val Phe Leu Arg Gln Lys Ser 1905 1910 1915 tcc acc tcc ctc agc aat ggc ggg gcc ata caa aac caa gag agt 5938 Ser Thr Ser Leu Ser Asn Gly Gly Ala Ile Gln Asn Gln Glu Ser 1920 1925 1930 ggc atc aaa gag tct gtc tcc tgg ggc act caa agg acc cag gat 5983 Gly Ile Lys Glu Ser Val Ser Trp Gly Thr Gln Arg Thr Gln Asp 1935 1940 1945 gca ccc cat gag gcc agg cca ccc ctg gag cgt ggc cac tcc aca 6028 Ala Pro His Glu Ala Arg Pro Pro Leu Glu Arg Gly His Ser Thr 1950 1955 1960 gag atc cct gtg ggg cgg tca gga gca ctg gct gtg gac gtt cag 6073 Glu Ile Pro Val Gly Arg Ser Gly Ala Leu Ala Val Asp Val Gln 1965 1970 1975 atg cag agc ata acc cgg agg ggc cct gat ggg gag ccc cag cct 6118 Met Gln Ser Ile Thr Arg Arg Gly Pro Asp Gly Glu Pro Gln Pro 1980 1985 1990 ggg ctg gag agc cag ggt cga gcg gcc tcc atg ccc cgc ctt gcg 6163 Gly Leu Glu Ser Gln Gly Arg Ala Ala Ser Met Pro Arg Leu Ala 1995 2000 2005 gcc gag act cag ccc gtc aca gat gcc agc ccc atg aag cgc tcc 6208 Ala Glu Thr Gln Pro Val Thr Asp Ala Ser Pro Met Lys Arg Ser 2010 2015 2020 atc tcc acg ctg gcc cag cgg ccc cgt ggg act cat ctt tgc agc 6253 Ile Ser Thr Leu Ala Gln Arg Pro Arg Gly Thr His Leu Cys Ser 2025 2030 2035 acc acc ccg gac cgc cca ccc cct agc cag gcg tcg tcg cac cac 6298 Thr Thr Pro Asp Arg Pro Pro Pro Ser Gln Ala Ser Ser His His 2040 2045 2050 cac cac cac cgc tgc cac cgc cgc agg gac agg aag cag agg tcc 6343 His His His Arg Cys His Arg Arg Arg Asp Arg Lys Gln Arg Ser 2055 2060 2065 ctg gag aag ggg ccc agc ctg tct gcc gat atg gat ggc gca cca 6388 Leu Glu Lys Gly Pro Ser Leu Ser Ala Asp Met Asp Gly Ala Pro 2070 2075 2080 agc agt gct gtg ggg ccg ggg ctg ccc ccg gga gag ggg cct aca 6433 Ser Ser Ala Val Gly Pro Gly Leu Pro Pro Gly Glu Gly Pro Thr 2085 2090 2095 ggc tgc cgg cgg gaa cga gag cgc cgg cag gag cgg ggc cgg tcc 6478 Gly Cys Arg Arg Glu Arg Glu Arg Arg Gln Glu Arg Gly Arg Ser 2100 2105 2110 cag gag cgg agg cag ccc tca tcc tcc tcc tcg gag aag cag cgc 6523 Gln Glu Arg Arg Gln Pro Ser Ser Ser Ser Ser Glu Lys Gln Arg 2115 2120 2125 ttc tac tcc tgc gac cgc ttt ggg ggc cgt gag ccc ccg aag ccc 6568 Phe Tyr Ser Cys Asp Arg Phe Gly Gly Arg Glu Pro Pro Lys Pro 2130 2135 2140 aag ccc tcc ctc agc agc cac cca acg tcg cca aca gct ggc cag 6613 Lys Pro Ser Leu Ser Ser His Pro Thr Ser Pro Thr Ala Gly Gln 2145 2150 2155 gag ccg gga ccc cac cca cag gcc ggc tca gcc gtg ggc ttt ccg 6658 Glu Pro Gly Pro His Pro Gln Ala Gly Ser Ala Val Gly Phe Pro 2160 2165 2170 aac aca acg ccc tgc tgc aga gag acc ccc tca gcc agc ccc tgg 6703 Asn Thr Thr Pro Cys Cys Arg Glu Thr Pro Ser Ala Ser Pro Trp 2175 2180 2185 ccc ctg gct ctc gaa ttg gct ctg acc ctt acc tgg ggc agc gtc 6748 Pro Leu Ala Leu Glu Leu Ala Leu Thr Leu Thr Trp Gly Ser Val 2190 2195 2200 tgg aca gtg agg cct ctg tcc acg ccc tgc ctg agg aca cgc tca 6793 Trp Thr Val Arg Pro Leu Ser Thr Pro Cys Leu Arg Thr Arg Ser 2205 2210 2215 ctt tcg agg agg ctg tgg cca cca act cgg gcc gct cct cca gga 6838 Leu Ser Arg Arg Leu Trp Pro Pro Thr Arg Ala Ala Pro Pro Gly 2220 2225 2230 ctt cct acg tgt cct ccc tga cctcccagtc tcaccctctc cgccgcgtgc 6889 Leu Pro Thr Cys Pro Pro 2235 ccaacggtta ccactgcacc ctgggactca gctcgggtgg ccgagcacgg cacagctacc 6949 accaccctga ccaagaccac tggtgctagc tgcaccgtga ccgctcagac gcctgcatgc 7009 agcaggcgtg tgttccagtg gatgagtttt atcatccaca cggggcagtc ggccctcggg 7069 ggaggccttg cccaccttgg tgaggctcct gtggcccctc cctccccctc ctcccctctt 7129 ttactctaga cgacgaataa agccctgttg cttgagtgta cgtaccgc 7177 34 2237 PRT Homo sapiens 34 Met Val Arg Phe Gly Asp Glu Leu Gly Gly Arg Tyr Gly Gly Pro Gly 1 5 10 15 Gly Gly Glu Arg Ala Arg Gly Gly Gly Ala Gly Gly Ala Gly Gly Pro 20 25 30 Gly Pro Gly Gly Leu Gln Pro Gly Gln Arg Val Leu Tyr Lys Gln Ser 35 40 45 Ile Ala Gln Arg Ala Arg Thr Met Ala Leu Tyr Asn Pro Ile Pro Val 50 55 60 Lys Gln Asn Cys Phe Thr Val Asn Arg Ser Leu Phe Val Phe Ser Glu 65 70 75 80 Asp Asn Val Val Arg Lys Tyr Ala Lys Arg Ile Thr Glu Trp Pro Pro 85 90 95 Phe Glu Tyr Met Ile Leu Ala Thr Ile Ile Ala Asn Cys Ile Val Leu 100 105 110 Ala Leu Glu Gln His Leu Pro Asp Gly Asp Lys Thr Pro Met Ser Glu 115 120 125 Arg Leu Asp Asp Thr Glu Pro Tyr Phe Ile Gly Ile Phe Cys Phe Glu 130 135 140 Ala Gly Ile Lys Ile Ile Ala Leu Gly Phe Val Phe His Lys Gly Ser 145 150 155 160 Tyr Leu Arg Asn Gly Trp Asn Val Met Asp Phe Val Val Val Leu Thr 165 170 175 Gly Ile Leu Ala Thr Ala Gly Thr Asp Phe Asp Leu Arg Thr Leu Arg 180 185 190 Ala Val Arg Val Leu Arg Pro Leu Lys Leu Val Ser Gly Ile Pro Ser 195 200 205 Leu Gln Val Val Leu Lys Ser Ile Met Lys Ala Met Val Pro Leu Leu 210 215 220 Gln Ile Gly Leu Leu Leu Phe Phe Ala Ile Leu Met Phe Ala Ile Ile 225 230 235 240 Gly Leu Glu Phe Tyr Met Gly Lys Phe His Lys Ala Cys Phe Pro Asn 245 250 255 Ser Thr Asp Ala Glu Pro Val Gly Asp Phe Pro Cys Gly Lys Glu Ala 260 265 270 Pro Ala Arg Leu Cys Glu Gly Asp Thr Glu Cys Arg Glu Tyr Trp Pro 275 280 285 Gly Pro Asn Phe Gly Ile Thr Asn Phe Asp Asn Ile Leu Phe Ala Ile 290 295 300 Leu Thr Val Phe Gln Cys Ile Thr Met Glu Gly Trp Thr Asp Ile Leu 305 310 315 320 Tyr Asn Thr Asn Asp Ala Ala Gly Asn Thr Trp Asn Trp Leu Tyr Phe 325 330 335 Ile Pro Leu Ile Ile Ile Gly Ser Phe Phe Met Leu Asn Leu Val Leu 340 345 350 Gly Val Leu Ser Gly Glu Phe Ala Lys Glu Arg Glu Arg Val Glu Asn 355 360 365 Arg Arg Ala Phe Leu Lys Leu Arg Arg Gln Gln Gln Ile Glu Arg Glu 370 375 380 Leu Asn Gly Tyr Leu Glu Trp Ile Phe Lys Ala Glu Glu Val Met Leu 385 390 395 400 Ala Glu Glu Asp Arg Asn Ala Glu Glu Lys Ser Pro Leu Asp Val Leu 405 410 415 Lys Arg Ala Ala Thr Lys Lys Ser Arg Asn Asp Leu Ile His Ala Glu 420 425 430 Glu Gly Glu Asp Arg Phe Ala Asp Leu Cys Ala Val Gly Ser Pro Phe 435 440 445 Ala Arg Ala Ser Leu Lys Ser Gly Lys Thr Glu Ser Ser Ser Tyr Phe 450 455 460 Arg Arg Lys Glu Lys Met Phe Arg Phe Phe Ile Arg Arg Met Val Lys 465 470 475 480 Ala Gln Ser Phe Tyr Trp Val Val Leu Cys Val Val Ala Leu Asn Thr 485 490 495 Leu Cys Val Ala Met Val His Tyr Asn Gln Pro Arg Arg Leu Thr Thr 500 505 510 Thr Leu Tyr Phe Ala Glu Phe Val Phe Leu Gly Leu Phe Leu Thr Glu 515 520 525 Met Ser Leu Lys Met Tyr Gly Leu Gly Pro Arg Ser Tyr Phe Arg Ser 530 535 540 Ser Phe Asn Cys Phe Asp Phe Gly Val Ile Val Gly Ser Val Phe Glu 545 550 555 560 Val Val Trp Ala Ala Ile Lys Pro Gly Ser Ser Phe Gly Ile Ser Val 565 570 575 Leu Arg Ala Leu Arg Leu Leu Arg Ile Phe Lys Val Thr Lys Tyr Trp 580 585 590 Ser Ser Leu Arg Asn Leu Val Val Ser Leu Leu Asn Ser Met Lys Ser 595 600 605 Ile Ile Ser Leu Leu Phe Leu Leu Phe Leu Phe Ile Val Val Phe Ala 610 615 620 Leu Leu Gly Met Gln Leu Phe Gly Gly Gln Phe Asn Phe Gln Asp Glu 625 630 635 640 Thr Pro Thr Thr Asn Phe Asp Thr Phe Pro Ala Ala Ile Leu Thr Val 645 650 655 Phe Gln Ile Leu Thr Gly Glu Asp Trp Asn Ala Val Met Tyr His Gly 660 665 670 Ile Glu Ser Gln Gly Gly Val Ser Lys Gly Met Phe Ser Ser Phe Tyr 675 680 685 Phe Ile Val Leu Thr Leu Phe Gly Asn Tyr Thr Leu Leu Asn Val Phe 690 695 700 Leu Ala Ile Ala Val Asp Asn Leu Ala Asn Ala Gln Glu Leu Thr Lys 705 710 715 720 Asp Glu Glu Glu Met Glu Glu Ala Ala Asn Gln Lys Leu Ala Leu Gln 725 730 735 Lys Ala Lys Glu Val Ala Glu Val Ser Pro Met Ser Ala Ala Asn Ile 740 745 750 Ser Ile Ala Ala Arg Gln Gln Asn Ser Ala Lys Ala Arg Ser Val Trp 755 760 765 Glu Gln Arg Ala Ser Gln Leu Arg Leu Gln Asn Leu Arg Ala Ser Cys 770 775 780 Glu Ala Leu Tyr Ser Glu Met Asp Pro Glu Glu Arg Leu Arg Phe Ala 785 790 795 800 Thr Thr Arg His Leu Arg Pro Asp Met Lys Thr His Leu Asp Arg Pro 805 810 815 Leu Val Val Glu Leu Gly Arg Asp Gly Ala Arg Gly Pro Val Gly Gly 820 825 830 Lys Ala Arg Pro Glu Ala Ala Glu Ala Pro Glu Gly Val Asp Pro Pro 835 840 845 Arg Arg His His Arg His Arg Asp Lys Asp Lys Thr Pro Ala Ala Gly 850 855 860 Asp Gln Asp Arg Ala Glu Ala Pro Lys Ala Glu Ser Gly Glu Pro Gly 865 870 875 880 Ala Arg Glu Glu Arg Pro Arg Pro His Arg Ser His Ser Lys Glu Ala 885 890 895 Ala Gly Pro Pro Glu Ala Arg Ser Glu Arg Gly Arg Gly Pro Gly Pro 900 905 910 Glu Gly Gly Arg Arg His His Arg Arg Gly Ser Pro Glu Glu Ala Ala 915 920 925 Glu Arg Glu Pro Arg Arg His Arg Ala His Arg His Gln Asp Pro Ser 930 935 940 Lys Glu Cys Ala Gly Ala Lys Gly Glu Arg Arg Ala Arg His Arg Gly 945 950 955 960 Gly Pro Arg Ala Gly Pro Arg Glu Ala Glu Ser Gly Glu Glu Pro Ala 965 970 975 Arg Arg His Arg Ala Arg His Lys Ala Gln Pro Ala His Glu Ala Val 980 985 990 Glu Lys Glu Thr Thr Glu Lys Glu Ala Thr Glu Lys Glu Ala Glu Ile 995 1000 1005 Val Glu Ala Asp Lys Glu Lys Glu Leu Arg Asn His Gln Pro Arg 1010 1015 1020 Glu Pro His Cys Asp Leu Glu Thr Ser Gly Thr Val Thr Val Gly 1025 1030 1035 Pro Met His Thr Leu Pro Ser Thr Cys Leu Gln Lys Val Glu Glu 1040 1045 1050 Gln Pro Glu Asp Ala Asp Asn Gln Arg Asn Val Thr Arg Met Gly 1055 1060 1065 Ser Gln Pro Pro Asp Pro Asn Thr Ile Val His Ile Pro Val Met 1070 1075 1080 Leu Thr Gly Pro Leu Gly Glu Ala Thr Val Val Pro Ser Gly Asn 1085 1090 1095 Val Asp Leu Glu Ser Gln Ala Glu Gly Lys Lys Glu Val Glu Ala 1100 1105 1110 Asp Asp Val Met Arg Ser Gly Pro Arg Pro Ile Val Pro Tyr Ser 1115 1120 1125 Ser Met Phe Cys Leu Ser Pro Thr Asn Leu Leu Arg Arg Phe Cys 1130 1135 1140 His Tyr Ile Val Thr Met Arg Tyr Phe Glu Val Val Ile Leu Val 1145 1150 1155 Val Ile Ala Leu Ser Ser Ile Ala Leu Ala Ala Glu Asp Pro Val 1160 1165 1170 Arg Thr Asp Ser Pro Arg Asn Asn Ala Leu Lys Tyr Leu Asp Tyr 1175 1180 1185 Ile Phe Thr Gly Val Phe Thr Phe Glu Met Val Ile Lys Met Ile 1190 1195 1200 Asp Leu Gly Leu Leu Leu His Pro Gly Ala Tyr Phe Arg Asp Leu 1205 1210 1215 Trp Asn Ile Leu Asp Phe Ile Val Val Ser Gly Ala Leu Val Ala 1220 1225 1230 Phe Ala Phe Ser Gly Ser Lys Gly Lys Asp Ile Asn Thr Ile Lys 1235 1240 1245 Ser Leu Arg Val Leu Arg Val Leu Arg Pro Leu Lys Thr Ile Lys 1250 1255 1260 Arg Leu Pro Lys Leu Lys Ala Val Phe Asp Cys Val Val Asn Ser 1265 1270 1275 Leu Lys Asn Val Leu Asn Ile Leu Ile Val Tyr Met Leu Phe Met 1280 1285 1290 Phe Ile Phe Ala Val Ile Ala Val Gln Leu Phe Lys Gly Lys Phe 1295 1300 1305 Phe Tyr Cys Thr Asp Glu Ser Lys Glu Leu Glu Arg Asp Cys Arg 1310 1315 1320 Gly Gln Tyr Leu Asp Tyr Glu Lys Glu Glu Val Glu Ala Gln Pro 1325 1330 1335 Arg Gln Trp Lys Lys Tyr Asp Phe His Tyr Asp Asn Val Leu Trp 1340 1345 1350 Ala Leu Leu Thr Leu Phe Thr Val Ser Thr Gly Glu Gly Trp Pro 1355 1360 1365 Met Val Leu Lys His Ser Val Asp Ala Thr Tyr Glu Glu Gln Gly 1370 1375 1380 Pro Ser Pro Gly Tyr Arg Met Glu Leu Ser Ile Phe Tyr Val Val 1385 1390 1395 Tyr Phe Val Val Phe Pro Phe Phe Phe Val Asn Ile Phe Val Ala 1400 1405 1410 Leu Ile Ile Ile Thr Phe Gln Glu Gln Gly Asp Lys Val Met Ser 1415 1420 1425 Glu Cys Ser Leu Glu Lys Asn Glu Arg Ala Cys Ile Asp Phe Ala 1430 1435 1440 Ile Ser Ala Lys Pro Leu Thr Arg Tyr Met Pro Gln Asn Arg Gln 1445 1450 1455 Ser Phe Gln Tyr Lys Thr Trp Thr Phe Val Val Ser Pro Pro Phe 1460 1465 1470 Glu Tyr Phe Ile Met Ala Met Ile Ala Leu Asn Thr Val Val Leu 1475 1480 1485 Met Met Lys Phe Tyr Asp Ala Pro Tyr Glu Tyr Glu Leu Met Leu 1490 1495 1500 Lys Cys Leu Asn Ile Val Phe Thr Ser Met Phe Ser Met Glu Cys 1505 1510 1515 Val Leu Lys Ile Ile Ala Phe Gly Val Leu Asn Tyr Phe Arg Asp 1520 1525 1530 Ala Trp Asn Val Phe Asp Phe Val Thr Val Leu Gly Ser Ile Thr 1535 1540 1545 Asp Ile Leu Val Thr Glu Ile Ala Glu Thr Asn Asn Phe Ile Asn 1550 1555 1560 Leu Ser Phe Leu Arg Leu Phe Arg Ala Ala Arg Leu Ile Lys Leu 1565 1570 1575 Leu Arg Gln Gly Tyr Thr Ile Arg Ile Leu Leu Trp Thr Phe Val 1580 1585 1590 Gln Ser Phe Lys Ala Leu Pro Tyr Val Cys Leu Leu Ile Ala Met 1595 1600 1605 Leu Phe Phe Ile Tyr Ala Ile Ile Gly Met Gln Val Phe Gly Asn 1610 1615 1620 Ile Ala Leu Asp Asp Asp Thr Ser Ile Asn Arg His Asn Asn Phe 1625 1630 1635 Arg Thr Phe Leu Gln Ala Leu Met Leu Leu Phe Arg Ser Ala Thr 1640 1645 1650 Gly Glu Ala Trp His Glu Ile Met Leu Ser Cys Leu Ser Asn Gln 1655 1660 1665 Ala Cys Asp Glu Gln Ala Asn Ala Thr Glu Cys Gly Ser Asp Phe 1670 1675 1680 Ala Tyr Phe Tyr Phe Val Ser Phe Ile Phe Leu Cys Ser Phe Leu 1685 1690 1695 Met Leu Asn Leu Phe Val Ala Val Ile Met Asp Asn Phe Glu Tyr 1700 1705 1710 Leu Thr Arg Asp Ser Ser Ile Leu Gly Pro His His Leu Asp Glu 1715 1720 1725 Phe Ile Arg Val Trp Ala Glu Tyr Asp Pro Ala Ala Cys Gly Arg 1730 1735 1740 Ile Ser Tyr Asn Asp Met Phe Glu Met Leu Lys His Met Ser Pro 1745 1750 1755 Pro Leu Gly Leu Gly Lys Lys Cys Pro Ala Arg Val Ala Tyr Lys 1760 1765 1770 Arg Leu Val Arg Met Asn Met Pro Ile Ser Asn Glu Asp Met Thr 1775 1780 1785 Val His Phe Thr Ser Thr Leu Met Ala Leu Ile Arg Thr Ala Leu 1790 1795 1800 Glu Ile Lys Leu Ala Pro Ala Gly Thr Lys Gln His Gln Cys Asp 1805 1810 1815 Ala Glu Leu Arg Lys Glu Ile Ser Val Val Trp Ala Asn Leu Pro 1820 1825 1830 Gln Lys Thr Leu Asp Leu Leu Val Pro Pro His Lys Pro Asp Glu 1835 1840 1845 Met Thr Val Gly Lys Val Tyr Ala Ala Leu Met Ile Phe Asp Phe 1850 1855 1860 Tyr Lys Gln Asn Lys Thr Thr Arg Asp Gln Met Gln Gln Ala Pro 1865 1870 1875 Gly Gly Leu Ser Gln Met Gly Pro Val Ser Leu Phe His Pro Leu 1880 1885 1890 Lys Ala Thr Leu Glu Gln Thr Gln Pro Ala Val Leu Arg Gly Ala 1895 1900 1905 Arg Val Phe Leu Arg Gln Lys Ser Ser Thr Ser Leu Ser Asn Gly 1910 1915 1920 Gly Ala Ile Gln Asn Gln Glu Ser Gly Ile Lys Glu Ser Val Ser 1925 1930 1935 Trp Gly Thr Gln Arg Thr Gln Asp Ala Pro His Glu Ala Arg Pro 1940 1945 1950 Pro Leu Glu Arg Gly His Ser Thr Glu Ile Pro Val Gly Arg Ser 1955 1960 1965 Gly Ala Leu Ala Val Asp Val Gln Met Gln Ser Ile Thr Arg Arg 1970 1975 1980 Gly Pro Asp Gly Glu Pro Gln Pro Gly Leu Glu Ser Gln Gly Arg 1985 1990 1995 Ala Ala Ser Met Pro Arg Leu Ala Ala Glu Thr Gln Pro Val Thr 2000 2005 2010 Asp Ala Ser Pro Met Lys Arg Ser Ile Ser Thr Leu Ala Gln Arg 2015 2020 2025 Pro Arg Gly Thr His Leu Cys Ser Thr Thr Pro Asp Arg Pro Pro 2030 2035 2040 Pro Ser Gln Ala Ser Ser His His His His His Arg Cys His Arg 2045 2050 2055 Arg Arg Asp Arg Lys Gln Arg Ser Leu Glu Lys Gly Pro Ser Leu 2060 2065 2070 Ser Ala Asp Met Asp Gly Ala Pro Ser Ser Ala Val Gly Pro Gly 2075 2080 2085 Leu Pro Pro Gly Glu Gly Pro Thr Gly Cys Arg Arg Glu Arg Glu 2090 2095 2100 Arg Arg Gln Glu Arg Gly Arg Ser Gln Glu Arg Arg Gln Pro Ser 2105 2110 2115 Ser Ser Ser Ser Glu Lys Gln Arg Phe Tyr Ser Cys Asp Arg Phe 2120 2125 2130 Gly Gly Arg Glu Pro Pro Lys Pro Lys Pro Ser Leu Ser Ser His 2135 2140 2145 Pro Thr Ser Pro Thr Ala Gly Gln Glu Pro Gly Pro His Pro Gln 2150 2155 2160 Ala Gly Ser Ala Val Gly Phe Pro Asn Thr Thr Pro Cys Cys Arg 2165 2170 2175 Glu Thr Pro Ser Ala Ser Pro Trp Pro Leu Ala Leu Glu Leu Ala 2180 2185 2190 Leu Thr Leu Thr Trp Gly Ser Val Trp Thr Val Arg Pro Leu Ser 2195 2200 2205 Thr Pro Cys Leu Arg Thr Arg Ser Leu Ser Arg Arg Leu Trp Pro 2210 2215 2220 Pro Thr Arg Ala Ala Pro Pro Gly Leu Pro Thr Cys Pro Pro 2225 2230 2235 35 6176 DNA Homo sapiens exon (1)..(17) Exon 41, continues 5′ to nt 1 35 tac gac ccg gct gcg tg gtaagtgagc cgtggtgctc tgtggtcctt 47 Tyr Asp Pro Ala Ala Cys 1 5 gggggtggtc catgcccata gatcttggga tgggcctggt ggcttcagac atgtttcaag 107 tgagcacccc ctcaggtttt ggtttggggc ctagggatct gtcctgtttc gtgtagagca 167 gcagtgatgt cccctccgag cagcacctcc cttttccatc tcgtgtgcct tcgcgcagtg 227 gcccggactg cataaagtga taagggtctt ttgagacctt gagttcagtt ccttgggagg 287 taccaggagt catggaaggt tttcaagggg cttgtgagac tcaggtcttc tgctgaaatt 347 tactgtcttc tttcaaggcc tgtcatgtga gggctcatgg agggcttgtg ggagggtgtg 407 tggagacagc acagccatag cgtccttgtg agactcgatg tagggtttta ggacattctc 467 cctaaggggc tcaggagtct ccctctgctc tttcttttgg ggacaggggc caacatgcac 527 ctctgtgtcc ccagcccagg ctgcatatag tgtgggtgct tggtgaactt ttttgacaga 587 tgagctacca ggaaggctgt agtgtgttta agacccttgt ctatcatctg tcatcgtggg 647 aaaggtttac ttgtttcaaa ggcgaggggt ggtgcctttc cagacagagg aggagtcgca 707 tgaagggcat ggtttgggtc agaaggtgaa gctgtttgag atcaggatcc atgggggtcc 767 cgtacagcat ggcatctcag cagggctgag agctcattcg ggaaggaaga caggtcaggc 827 agcatggctt ctccatcttt ctgtttgtcc attccttcca tcactcgttc ctcatttact 887 tgctcgctca ctcactcaag caatgtctac tgtgggctgc tccctgcaag gccactaggc 947 ctgctagcac ctcactcaca gcgtgtgccc gggaaatgat cgtggatgag cagctctcag 1007 tgagtgcgta gacatccacc actccccgtg ccctaggggg atgagggaac ygtgggtgcc 1067 accgaggcct gccttctctc tctgagctcc ttagcctgcc caggccccct cgcactcctc 1127 tgcccccagt gcccttactg ggggagggcc ggcaggacgt ggtcagaccc ctcatggtga 1187 ggtcctactg cccacagagc tcctgggttc tgcctggttt tgcttaaact gcagctcagc 1247 agagggagcc ctccacagac acaaaaggcc tgggagcccg actagacttc cccaccctcc 1307 tttccactca gcctcccsgg agcaccccca ccttcctagt gaggatccag agggtgctgc 1367 acgggccctt cccagtctgg acaaggtcca gagccactgg cagcatcggg ggccctggga 1427 tggggcctct cctgtccagg ctcttccagg cacacagcat ctctgtgggt gtttttcatt 1487 tgagtcggaa atatacagtt tttacgcagt gcaaaacaga cgtagagatt gtctgtgttt 1547 cacagtgtat atgacaattt ccgtggcttg cgagaaccct gtcatgtccg atgcagcaat 1607 atgtttgccc tgtgatactt acttcatgct gggagggaca ggctcaggca cattcacaca 1667 ggacctgtgg tcaagtaagc ccagtcgacc tgggggagac tgaccacatt gaagacctag 1727 accttgttag gcaaagggca ggagagactc cagccgaggc aggatttagg tgaattctag 1787 gcaggtcacc ctgaatgtgt ggtttagaga gtcgctgctt tttctgggtg tattttttct 1847 rgaggagact gtgttgcaga aaacagagat actttatagc atgtagttag tactraaggg 1907 caaaggcaga tcaacaaagg cctgtgagag gatgacaaca ttccccaatc tttatgagct 1967 acgcccgggc cttccacagt cagccgccgg caagagcaga ggcaggaaga acgggaagtg 2027 gacttgggcc agatggcagc ttggttacca tgcacagtgg taccatacca aagccagagt 2087 ctcagagcag gggtccttag aagacatagg cagtcgggga tgtgagaagt gcttactgaa 2147 gagtaaacaa cagaatacag gcctcacccc agagatagca cgcacaaaat aacacacaaa 2207 acctgcgggc cttgagatag cacagacgtg acctgtgagc aacacatgat tctgccccca 2267 cgagcagcct gggctcaccc tacgtagtcc aagatggcca ggacaggccg aggggcccag 2327 cagaggcagc tgagcagatt gggcctggat cctgtgtcct gagcagagca cagggcacct 2387 tgagcctttt tggtagcctc tgtgacaaac gcagtgatgt agtcatttcc caggggacca 2447 ctctatggct cctcgttctt tgggagaaac tttgaaacaa caacaaaatt ttatgagatt 2507 tcctgagttg tgtgtgcaca tgtgtggtgc acaaacagga catgtgtgca tgtacatggc 2567 tgtgttgtgt gcgtgtttgc acagtgtgac cacatgtgca ctctgtgcat gtgtacatgt 2627 gtgttgtgca cgcatgcaca cagatgtcta catgtgtgtt ttgtgcacat gtgcatgcac 2687 aaggcgcgca cgtgtgtgca tgttgacgtt tgtgtgtgca catatgattg tatatatgtg 2747 tgcctgtgtg tatatgtgtg caagtgaact gaatgtgcgt gcatgcctgt gtggttgtat 2807 gtggatgtgt gtatgaatga catgtgcacc tgtgtgtgca tatgcccatg tgtgcatgtg 2867 tgtgcctgtg gatgtgcaca tgcccgtgtg tgcctgtggt gtgcacgtgt ctgtggtgtg 2927 cacgtgcctg tgtgtgcatg tgcctttgtg tgtgtgccac cgtggtgcgt atgtgcctgt 2987 gtgtgcctgt gggtgtgcac gtgcctgtgg tgtactcgtg cctgtggtgt gcatgtgcct 3047 gtggtgtgca tgtgcctgtg gtgcgcatgt gcctgtgtgg gtgtgcatgt gtgtgcctgt 3107 gggtgtgcac atgtctgtgg tgtacacgtg cctgtggtgc gcatgtgcct gtgtcggtgg 3167 attctgaagg cacgaaactg ttcaccctgg tgctgctttt cccagccttc ctattgttgt 3227 tgcttcaacc ctgtggtgtg aagcctggtg acttgagagg agaattgcag tcacacttct 3287 tgcagcaatc tggctgctca tttctgtgtc cacccatctg tctaataaca tctcctgggc 3347 atctgccatg tgctggggca ggggcccaaa ggtgaaacag gcacatgctg tcagaacact 3407 cagccaggct tggcagtgag accacatggt gactgtagct caaggccagg gcatttctga 3467 ggaaggagag gccatgtctg gcctgaagaa tgagaggagg tgccatttga gctgaactta 3527 aaggaatagg aaggattgag cactagagaa ataggatgga ttgagctggg gatgggaggt 3587 ggggcagagg gaagagggag gccaggtggc ttctgtcagg ctggagagga gagtgcattg 3647 cagaggggct gcaaggaagg ctgagaccgt ttgagaaagg cattgaaatt ggttgaacaa 3707 gtcgctttga ttttgcgttg tagacagtgg gctcagtcct tgcatcgagg agtgatggtg 3767 tcaggcccac actttccacc tgggcttgat gggcagggac agctggggag ggtggggggt 3827 ctcacgtgtg tccagccccc cgtggtggtc ccttggctgc cacaacctta gcaaacatct 3887 ttggtgaggc cgaggtgggg cttcctgttt cttccctttt acagaaggaa attcaacatg 3947 atttggagct gattggaccg agggggctac actgtaggag agaggagcat tggtggtgat 4007 ccaaggatgc cagcctacga tgagaggagg tccttagctg gaccagggct tccaggggag 4067 gacacagagt gttcagggag acagggtcag tcaggaggca aatgggtatg ggcctctgag 4127 gttgctgtga tagagaagca gacctgcctt gctgtggtgg tgagaaagcc aggcgtcaga 4187 gggtttggct gacctgggag gcccagggag catcgtcact cagggagtga gaggaagagc 4247 tgaccgagag ggaggggcag ggcagtgttc tgtgtggagc ggctcctgca cacatcgggc 4307 tccggaaatt tcgctggggt tgccacacct cccggggagc tccaagcccc agtaccccgg 4367 cgaggtgcca cctgtccagt gcacccctca cctccgccgc cacgcctgcg cgaggtcggt 4427 cttcccatca caggctgggc gggcgggagg gtcgggctcc atcctgcctt tgttgccata 4487 acctgtgaca tttcctttcc ag t tgc cgg att cat tat aag gat atg tac 4537 Cys Arg Ile His Tyr Lys Asp Met Tyr 10 15 agt ttg ttg cgt tgt att gcg cca ccc gtt ggc tta ggg aag aac tgc 4585 Ser Leu Leu Arg Cys Ile Ala Pro Pro Val Gly Leu Gly Lys Asn Cys 20 25 30 cct cgt agg ttg gcc tac aag gtttgcaact tcagagcctc catccaacat 4636 Pro Arg Arg Leu Ala Tyr Lys 35 acttccctgc ccgaaacgca cacagcacac actccctgcc tggtttggga atgacgacgc 4696 ctcacctttc tttcctcctg tcctgccccg cactccagcc tcctggacgc tttggttccc 4756 tgtctaatct cccctgaccc ttctagctgg ctggggacag gcagcctttt gagagtgcac 4816 agaaagcttt ctggttggga tcagctagct gggtgggaga tgggggctag gtccctcctg 4876 catcaaggaa gcagccgact tgcccggttt ttcctccgag ctctcgagag tgagctgatg 4936 gtcaggccaa aggccgaggg ccccagagga agggagcacg ggcacaggcc tcccaggagc 4996 agccgtcctc tgggttggaa gagcccagta acccagtggc tctccagtcc ctgggggagg 5056 aaagggcaga ggcagagtgg gggccaaaga caagccgtcc tgctttgcct ctggagtgat 5116 gcgctcagct cagccaagga gcccctggtc tggaaccgtg ggaggagggc aaggccccag 5176 ggcagatcca tctgccagga agaggctgtc ccctttctct cctgggccac ctgaatctgg 5236 ctgtgtctct aggaccccaa gcccacaggc aggtgtccca gggttggagg taggccccag 5296 gcctcgtggc ctctctactt gggaagactc tgtcatcgga gcctttaggt tcctagatcc 5356 tgcaacctgc ccctttgctg tcagagctgg tgcaaggtgg ccccaggcca tgtcctgcca 5416 gctcctcccc cctcccgcag tctcccattt cccacccagc cctgagcccc agcagcagcc 5476 ctgccctggg ctggcctcgg gcgtctctgg gcttgaagca ggacttgccc caaggttagg 5536 ttttggctgt acagcttcag ggctccctgt ttagttttct ggtttgtttc agatcttctc 5596 caccttttta gcctctagcc tcacttggaa gcaaatctga ccgtgaggaa agctgatgtc 5656 tctgccgtgg ttctcagcca ctgcctcatc tgccacctga ccctgcctgc cagctcttct 5716 ggcagggtgg accagctctt ttctgattgg cattcactgt gatttttaaa agagtaaaat 5776 cagaaattat caacccaaag ccgccccgat gcagcccttc ctcacccctc catgttcatt 5836 agctcagacg ccacccccgc ccactgcccc gcgtggggct ggagtgagga ggtgaggctc 5896 gggggtgggg ggccaggagg gggtcaagcc aagcagagaa atccctcatt ttatttattt 5956 tgattttggg ctttgaatcc gacactttga ttaactggct ctgttttctt gtctgcttcc 6016 tccctgcccc taccccgctc ccctccccgc tcccctcctg ctgccgctcc tcctgtggac 6076 caccccactg tgccctggcc tcgctgggac gggtttccag tgg gcg cat cag tta 6131 Trp Ala His Gln Leu 40 caa tga cat gtt tga gat gct gaa aca cat gtc ccc gcc tct ggg 6176 Gln His Val Asp Ala Glu Thr His Val Pro Ala Ser Gly 45 50 55 36 38 PRT Homo sapiens 36 Tyr Asp Pro Ala Ala Cys Cys Arg Ile His Tyr Lys Asp Met Tyr Ser 1 5 10 15 Leu Leu Arg Cys Ile Ala Pro Pro Val Gly Leu Gly Lys Asn Cys Pro 20 25 30 Arg Arg Leu Ala Tyr Lys 35 37 6984 DNA Mus musculus CDS (1)..(6984) 37 atg gtc cgc ttc ggg gac gag cta ggc ggc cgc tat ggg ggc acc ggc 48 Met Val Arg Phe Gly Asp Glu Leu Gly Gly Arg Tyr Gly Gly Thr Gly 1 5 10 15 ggc ggg gag cgg gct cgg ggc ggc ggg gcc ggc ggg gcg ggt ggc ccg 96 Gly Gly Glu Arg Ala Arg Gly Gly Gly Ala Gly Gly Ala Gly Gly Pro 20 25 30 ggc cag ggg ggt ctg ccg ccg ggc cag cgg gtc ctg tac aag cag tcc 144 Gly Gln Gly Gly Leu Pro Pro Gly Gln Arg Val Leu Tyr Lys Gln Ser 35 40 45 att gcg cag cgc gca cgg act atg gcc ctg tac aac ccc atc cca gtc 192 Ile Ala Gln Arg Ala Arg Thr Met Ala Leu Tyr Asn Pro Ile Pro Val 50 55 60 aag cag aac tgc ttc acc gtc aac cgc tcg ctc ttc gtc ttc agc gag 240 Lys Gln Asn Cys Phe Thr Val Asn Arg Ser Leu Phe Val Phe Ser Glu 65 70 75 80 gac aac gtc gtc cgc aaa tac gct aag cgc atc acc gaa tgg ccg ccc 288 Asp Asn Val Val Arg Lys Tyr Ala Lys Arg Ile Thr Glu Trp Pro Pro 85 90 95 ttc gaa tac atg atc ctg gcc acc atc atc gcc aac tgt att gtt ctg 336 Phe Glu Tyr Met Ile Leu Ala Thr Ile Ile Ala Asn Cys Ile Val Leu 100 105 110 gcc ctg gag cag cac ctc cct gat ggg gac aag act ccc atg tct gag 384 Ala Leu Glu Gln His Leu Pro Asp Gly Asp Lys Thr Pro Met Ser Glu 115 120 125 cga cta gat gac acg gag cct tac ttc atc ggg atc ttt tgc ttc gag 432 Arg Leu Asp Asp Thr Glu Pro Tyr Phe Ile Gly Ile Phe Cys Phe Glu 130 135 140 gcg ggc atc aag atc ata gcc ctg ggc ttt gtt ttc cac aag ggc tcc 480 Ala Gly Ile Lys Ile Ile Ala Leu Gly Phe Val Phe His Lys Gly Ser 145 150 155 160 tac ctt cgg aac ggc tgg aat gtc atg gac ttc gtg gtg gtc ctc acg 528 Tyr Leu Arg Asn Gly Trp Asn Val Met Asp Phe Val Val Val Leu Thr 165 170 175 ggg att ctc gcc aca gct gga act gac ttt gac ctg cgc aca ctg agg 576 Gly Ile Leu Ala Thr Ala Gly Thr Asp Phe Asp Leu Arg Thr Leu Arg 180 185 190 gct gtg cgt gtg ctt agg ccc ctg aag ctg gtg tct gga att cca agc 624 Ala Val Arg Val Leu Arg Pro Leu Lys Leu Val Ser Gly Ile Pro Ser 195 200 205 ttg cag gtg gtg ctt aag tcc atc atg aag gcc atg gtc ccg ctg ctg 672 Leu Gln Val Val Leu Lys Ser Ile Met Lys Ala Met Val Pro Leu Leu 210 215 220 cag att ggg ctg ctg ctc ttc ttt gcc atc ctc atg ttt gcc atc atc 720 Gln Ile Gly Leu Leu Leu Phe Phe Ala Ile Leu Met Phe Ala Ile Ile 225 230 235 240 ggc ctc gaa ttc tat atg ggc aaa ttc cat aag gcc tgt ttc ccc aac 768 Gly Leu Glu Phe Tyr Met Gly Lys Phe His Lys Ala Cys Phe Pro Asn 245 250 255 agc aca gat aca gag cct gtg ggt gac ttt ccc tgt ggc aaa gat ccc 816 Ser Thr Asp Thr Glu Pro Val Gly Asp Phe Pro Cys Gly Lys Asp Pro 260 265 270 cct gct cgt cag tgt gat ggt gac acc gaa tgc cgg gag tac tgg cca 864 Pro Ala Arg Gln Cys Asp Gly Asp Thr Glu Cys Arg Glu Tyr Trp Pro 275 280 285 gga ccc aac ttt ggc atc acc aat ttt gac aac atc ctg ttt gcc atc 912 Gly Pro Asn Phe Gly Ile Thr Asn Phe Asp Asn Ile Leu Phe Ala Ile 290 295 300 ttg aca gtg ttc cag tgt atc acc atg gag ggc tgg act gac atc ctc 960 Leu Thr Val Phe Gln Cys Ile Thr Met Glu Gly Trp Thr Asp Ile Leu 305 310 315 320 tac aat aca aat gat gcg gct ggc aac aca tgg aac tgg ttg tac ttc 1008 Tyr Asn Thr Asn Asp Ala Ala Gly Asn Thr Trp Asn Trp Leu Tyr Phe 325 330 335 atc ccc ctc atc atc att ggc tcc ttc ttc atg ctc aac ctg gtg ctg 1056 Ile Pro Leu Ile Ile Ile Gly Ser Phe Phe Met Leu Asn Leu Val Leu 340 345 350 ggt gtg ctt tcc gga gag ttt gcc aag gag cgg gag cga gtc gag aac 1104 Gly Val Leu Ser Gly Glu Phe Ala Lys Glu Arg Glu Arg Val Glu Asn 355 360 365 cgc cgc gcc ttc ctg aag ctc cgc agg cag cag cag att gag cga gag 1152 Arg Arg Ala Phe Leu Lys Leu Arg Arg Gln Gln Gln Ile Glu Arg Glu 370 375 380 ctg aat ggg tac ttg gag tgg atc ttc aag gca gag gaa gtc atg ttg 1200 Leu Asn Gly Tyr Leu Glu Trp Ile Phe Lys Ala Glu Glu Val Met Leu 385 390 395 400 gca gag gag gac aag aat gca gaa gag aaa tcc cct ttg gat gtg ttg 1248 Ala Glu Glu Asp Lys Asn Ala Glu Glu Lys Ser Pro Leu Asp Val Leu 405 410 415 aag aga gct gcc acc aag aag agc cga aat gac ctc atc cat gca gaa 1296 Lys Arg Ala Ala Thr Lys Lys Ser Arg Asn Asp Leu Ile His Ala Glu 420 425 430 gag ggg gag gac cgg ttt gta gac ctc tgt gca gtt ggg tct cca ttt 1344 Glu Gly Glu Asp Arg Phe Val Asp Leu Cys Ala Val Gly Ser Pro Phe 435 440 445 gct cgt gcc agc ctc aag agt ggg aag acg gag agc tca tcg tac ttc 1392 Ala Arg Ala Ser Leu Lys Ser Gly Lys Thr Glu Ser Ser Ser Tyr Phe 450 455 460 cgg aga aag gag aag atg ttc cgg ttc ttt atc cgg cgt atg gtg aaa 1440 Arg Arg Lys Glu Lys Met Phe Arg Phe Phe Ile Arg Arg Met Val Lys 465 470 475 480 gca cag agc ttc tac tgg gtg gta ctg tgt gtg gtg gcc ctg aac aca 1488 Ala Gln Ser Phe Tyr Trp Val Val Leu Cys Val Val Ala Leu Asn Thr 485 490 495 ctg tgt gtg gcc atg gtg cac tat aat cag cct cag cgg ctt acc act 1536 Leu Cys Val Ala Met Val His Tyr Asn Gln Pro Gln Arg Leu Thr Thr 500 505 510 gca ctg tac ttt gca gag ttt gtt ttc ctg ggt ctc ttc ctc aca gag 1584 Ala Leu Tyr Phe Ala Glu Phe Val Phe Leu Gly Leu Phe Leu Thr Glu 515 520 525 atg tcc ctg aag atg tat ggc cta ggg ccc aga agt tac ttc agg tct 1632 Met Ser Leu Lys Met Tyr Gly Leu Gly Pro Arg Ser Tyr Phe Arg Ser 530 535 540 tcc ttc aac tgc ttt gac ttt ggg gtg att gtg ggg agt atc ttt gaa 1680 Ser Phe Asn Cys Phe Asp Phe Gly Val Ile Val Gly Ser Ile Phe Glu 545 550 555 560 gta gtc tgg gct gcc atc aag cca gga acc tcc ttt gga atc agt gtg 1728 Val Val Trp Ala Ala Ile Lys Pro Gly Thr Ser Phe Gly Ile Ser Val 565 570 575 ctg cgg gct ctg cga ctg ctg agg ata ttc aaa gtt acc aag tat tgg 1776 Leu Arg Ala Leu Arg Leu Leu Arg Ile Phe Lys Val Thr Lys Tyr Trp 580 585 590 aac tct ctg agg aac ctg gtg gtt tcc ctc ctc aat tcc atg aag tcc 1824 Asn Ser Leu Arg Asn Leu Val Val Ser Leu Leu Asn Ser Met Lys Ser 595 600 605 atc atc agc ctt ctc ttc ctg ctt ttc ctc ttc atc gtg gtc ttc gct 1872 Ile Ile Ser Leu Leu Phe Leu Leu Phe Leu Phe Ile Val Val Phe Ala 610 615 620 ctg ttg ggg atg cag ctg ttt ggg gga cag ttc aac ttt caa gat gag 1920 Leu Leu Gly Met Gln Leu Phe Gly Gly Gln Phe Asn Phe Gln Asp Glu 625 630 635 640 act cca acc acc aat ttt gat acc ttc cca gct gcc atc ctc act gtc 1968 Thr Pro Thr Thr Asn Phe Asp Thr Phe Pro Ala Ala Ile Leu Thr Val 645 650 655 ttt cag atc ctg aca gga gag gat tgg aat gcc gta atg tat cat ggg 2016 Phe Gln Ile Leu Thr Gly Glu Asp Trp Asn Ala Val Met Tyr His Gly 660 665 670 att gag tcg caa ggt gga gtc agc aaa ggc atg ttt tct tcc ttt tac 2064 Ile Glu Ser Gln Gly Gly Val Ser Lys Gly Met Phe Ser Ser Phe Tyr 675 680 685 ttc atc gtc ctg aca ctg ttt gga aac tac acc ctg ctg aat gtt ttt 2112 Phe Ile Val Leu Thr Leu Phe Gly Asn Tyr Thr Leu Leu Asn Val Phe 690 695 700 ctg gcc att gct gtg gac aac ctt gcc aat gcc cag gag ttg acc aag 2160 Leu Ala Ile Ala Val Asp Asn Leu Ala Asn Ala Gln Glu Leu Thr Lys 705 710 715 720 gat gaa gag gag atg gaa gaa gca gcc aat cag aaa ctt gct ctt cag 2208 Asp Glu Glu Glu Met Glu Glu Ala Ala Asn Gln Lys Leu Ala Leu Gln 725 730 735 aag gcc aaa gaa gta gct gaa gtc agc ccc atg tct gct gcc aat atc 2256 Lys Ala Lys Glu Val Ala Glu Val Ser Pro Met Ser Ala Ala Asn Ile 740 745 750 tcc atc gct gcc agg cag cag aac tcg gcc aag gcg cgc tca gta tgg 2304 Ser Ile Ala Ala Arg Gln Gln Asn Ser Ala Lys Ala Arg Ser Val Trp 755 760 765 gag cag cgg gcc agt cag cta agg ctc cag aat ctg cgt gcc agc tgt 2352 Glu Gln Arg Ala Ser Gln Leu Arg Leu Gln Asn Leu Arg Ala Ser Cys 770 775 780 gag gca ttg tac agt gag atg gac cct gag gag cgc ctg cgt tat gcc 2400 Glu Ala Leu Tyr Ser Glu Met Asp Pro Glu Glu Arg Leu Arg Tyr Ala 785 790 795 800 agc acg cgc cat gtg agg cca gac atg aag aca cac atg gac cga ccc 2448 Ser Thr Arg His Val Arg Pro Asp Met Lys Thr His Met Asp Arg Pro 805 810 815 cta gtg gtg gag cct ggt cga gat ggc ttg cgg gga ccc gtt ggg agc 2496 Leu Val Val Glu Pro Gly Arg Asp Gly Leu Arg Gly Pro Val Gly Ser 820 825 830 aag tca aag cct gaa ggc acg gag gcc aca gaa agc gcg gac cta cct 2544 Lys Ser Lys Pro Glu Gly Thr Glu Ala Thr Glu Ser Ala Asp Leu Pro 835 840 845 cgc cgg cac cac cgg cat cgt gat agg gac aag acc tca gcc aca gca 2592 Arg Arg His His Arg His Arg Asp Arg Asp Lys Thr Ser Ala Thr Ala 850 855 860 cct gct gga ggc gaa cag gac agg aca gaa agc acc gag acc ggg gcc 2640 Pro Ala Gly Gly Glu Gln Asp Arg Thr Glu Ser Thr Glu Thr Gly Ala 865 870 875 880 cgg gag gaa cgt gcg cgc cct cgt cga agt cac agc aag gag act cca 2688 Arg Glu Glu Arg Ala Arg Pro Arg Arg Ser His Ser Lys Glu Thr Pro 885 890 895 ggg gct gac acg caa gtg cgc tgt gag cgc agt agg cgt cac cac cgg 2736 Gly Ala Asp Thr Gln Val Arg Cys Glu Arg Ser Arg Arg His His Arg 900 905 910 cgc ggc tcc ccg gag gag gcc act gaa cgg gag cct cgg cgc cac cgt 2784 Arg Gly Ser Pro Glu Glu Ala Thr Glu Arg Glu Pro Arg Arg His Arg 915 920 925 gcc cac cgg cat gca cag gac tca agc aag gag ggc acg gcg ccg gtg 2832 Ala His Arg His Ala Gln Asp Ser Ser Lys Glu Gly Thr Ala Pro Val 930 935 940 ctt gta ccc aag ggt gag cga cga gca aga cac cga ggc cca cgc acg 2880 Leu Val Pro Lys Gly Glu Arg Arg Ala Arg His Arg Gly Pro Arg Thr 945 950 955 960 ggt cca cgt gag gca gag aac aac gag gag ccc aca cgc agg cac cgt 2928 Gly Pro Arg Glu Ala Glu Asn Asn Glu Glu Pro Thr Arg Arg His Arg 965 970 975 gca agg cat aag gtg cca ccc aca ctg cag ccc cca gag agg gag gct 2976 Ala Arg His Lys Val Pro Pro Thr Leu Gln Pro Pro Glu Arg Glu Ala 980 985 990 gca gag aag gag agc aac gcg gtg gaa ggg gat aag gaa acc cga aat 3024 Ala Glu Lys Glu Ser Asn Ala Val Glu Gly Asp Lys Glu Thr Arg Asn 995 1000 1005 cac cag ccc aag gaa cct cac tgt gac ctg gag gcc att gca gtt 3069 His Gln Pro Lys Glu Pro His Cys Asp Leu Glu Ala Ile Ala Val 1010 1015 1020 aca ggt gtg ggc cct ctg cac atg ctg ccc agc acc tgt ctc cag 3114 Thr Gly Val Gly Pro Leu His Met Leu Pro Ser Thr Cys Leu Gln 1025 1030 1035 aaa gtg gac gag caa cca gag gat gca gac aac cag cgt aat gtc 3159 Lys Val Asp Glu Gln Pro Glu Asp Ala Asp Asn Gln Arg Asn Val 1040 1045 1050 acc cgg atg ggc agt cag ccc tca gat ccc agc acc act gtg cat 3204 Thr Arg Met Gly Ser Gln Pro Ser Asp Pro Ser Thr Thr Val His 1055 1060 1065 gtc cca gtg aca ctg aca ggc cct cct ggg gag acc cct gta gtt 3249 Val Pro Val Thr Leu Thr Gly Pro Pro Gly Glu Thr Pro Val Val 1070 1075 1080 ccc agt ggt aac atg aac ctg gaa ggc caa gca gag ggc aag aag 3294 Pro Ser Gly Asn Met Asn Leu Glu Gly Gln Ala Glu Gly Lys Lys 1085 1090 1095 gag gca gag gcg gat gat gtg ctg aga aga ggc ccc agg ccc atc 3339 Glu Ala Glu Ala Asp Asp Val Leu Arg Arg Gly Pro Arg Pro Ile 1100 1105 1110 gtt ccc tac agc tcc atg ttt tgt ctc agc ccc acc aac ctg ctt 3384 Val Pro Tyr Ser Ser Met Phe Cys Leu Ser Pro Thr Asn Leu Leu 1115 1120 1125 cgt cgc ttc tgc cat tac att gtg acc atg cgg tac ttt gag atg 3429 Arg Arg Phe Cys His Tyr Ile Val Thr Met Arg Tyr Phe Glu Met 1130 1135 1140 gta att ctt gtg gtc att gcc ttg agc agc att gcc ctg gct gca 3474 Val Ile Leu Val Val Ile Ala Leu Ser Ser Ile Ala Leu Ala Ala 1145 1150 1155 gag gat cct gtg cgg aca gat tca ttc agg aac aac gct tta aag 3519 Glu Asp Pro Val Arg Thr Asp Ser Phe Arg Asn Asn Ala Leu Lys 1160 1165 1170 tac atg gat tac atc ttt aca gga gtc ttc acc ttt gaa atg gtc 3564 Tyr Met Asp Tyr Ile Phe Thr Gly Val Phe Thr Phe Glu Met Val 1175 1180 1185 ata aag atg ata gac ttg ggc ttg ctg ctg cac cct ggt gcc tac 3609 Ile Lys Met Ile Asp Leu Gly Leu Leu Leu His Pro Gly Ala Tyr 1190 1195 1200 ttc cgg gac ctg tgg aac att ctg gac ttc atc gtt gtc agt gga 3654 Phe Arg Asp Leu Trp Asn Ile Leu Asp Phe Ile Val Val Ser Gly 1205 1210 1215 gcc ctg gtg gca ttt gcg ttc tcg agc ttc atg gga gga tcc aaa 3699 Ala Leu Val Ala Phe Ala Phe Ser Ser Phe Met Gly Gly Ser Lys 1220 1225 1230 ggg aaa gac atc aat acc atc aag tct ctg aga gtc ctg cgt gtc 3744 Gly Lys Asp Ile Asn Thr Ile Lys Ser Leu Arg Val Leu Arg Val 1235 1240 1245 ctg agg ccc ctc aag acc atc aag cgg ctg cct aag ctc aag gct 3789 Leu Arg Pro Leu Lys Thr Ile Lys Arg Leu Pro Lys Leu Lys Ala 1250 1255 1260 gtc ttt gac tgt gtg gtg aac tcc ctg aag aac gtc ttg aac atc 3834 Val Phe Asp Cys Val Val Asn Ser Leu Lys Asn Val Leu Asn Ile 1265 1270 1275 ctg att gtc tac atg ctc ttc atg ttc ata ttt gcc gtc att gcc 3879 Leu Ile Val Tyr Met Leu Phe Met Phe Ile Phe Ala Val Ile Ala 1280 1285 1290 gtc cag ctc ttc aaa ggg aag ttc ttt tac tgt act gat gaa tcc 3924 Val Gln Leu Phe Lys Gly Lys Phe Phe Tyr Cys Thr Asp Glu Ser 1295 1300 1305 aag gag ctg gag agg gac tgc cgg ggt cag tat ttg gat tat gag 3969 Lys Glu Leu Glu Arg Asp Cys Arg Gly Gln Tyr Leu Asp Tyr Glu 1310 1315 1320 aag gaa gaa gta gaa gcc cag cca agg cag tgg aag aaa tat gac 4014 Lys Glu Glu Val Glu Ala Gln Pro Arg Gln Trp Lys Lys Tyr Asp 1325 1330 1335 ttc cac tat gac aat gtt ctc tgg gcc ttg ttg acg ctg ttc aca 4059 Phe His Tyr Asp Asn Val Leu Trp Ala Leu Leu Thr Leu Phe Thr 1340 1345 1350 gtg tcc acg gga gag ggg tgg ccc atg gtg ctg aaa cac tct gtg 4104 Val Ser Thr Gly Glu Gly Trp Pro Met Val Leu Lys His Ser Val 1355 1360 1365 gat gcc acc tat gag gaa cag ggg ccc agt ccc ggg ttc cgg atg 4149 Asp Ala Thr Tyr Glu Glu Gln Gly Pro Ser Pro Gly Phe Arg Met 1370 1375 1380 gag ctc tcc atc ttc tac gtg gtc tac ttt gtg gtc ttc cct ttt 4194 Glu Leu Ser Ile Phe Tyr Val Val Tyr Phe Val Val Phe Pro Phe 1385 1390 1395 ttc ttt gtc aac atc ttt gtg gcc ttg atc att atc acc ttc cag 4239 Phe Phe Val Asn Ile Phe Val Ala Leu Ile Ile Ile Thr Phe Gln 1400 1405 1410 gaa cag gga gat aag gtg atg tct gaa tgc agc tta gaa aag aat 4284 Glu Gln Gly Asp Lys Val Met Ser Glu Cys Ser Leu Glu Lys Asn 1415 1420 1425 gag agg gct tgc att gat ttt gcc atc agt gcc aag ccc ctg aca 4329 Glu Arg Ala Cys Ile Asp Phe Ala Ile Ser Ala Lys Pro Leu Thr 1430 1435 1440 cgg tac atg cct caa aac aaa cag tcg ttc cag tat aag aca tgg 4374 Arg Tyr Met Pro Gln Asn Lys Gln Ser Phe Gln Tyr Lys Thr Trp 1445 1450 1455 aca ttc gtg gtc tct cca ccc ttt gag tac ttc atc atg gct atg 4419 Thr Phe Val Val Ser Pro Pro Phe Glu Tyr Phe Ile Met Ala Met 1460 1465 1470 ata gcc ctc aac aca gtg gtg ctg atg atg aag ttc tat gat gca 4464 Ile Ala Leu Asn Thr Val Val Leu Met Met Lys Phe Tyr Asp Ala 1475 1480 1485 cct tat gag tac gag ctg atg ctg aaa tgc ctg aac att gtc ttc 4509 Pro Tyr Glu Tyr Glu Leu Met Leu Lys Cys Leu Asn Ile Val Phe 1490 1495 1500 aca tcc atg ttc tcg atg gag tgc ata ctg aag atc atc gcc ttt 4554 Thr Ser Met Phe Ser Met Glu Cys Ile Leu Lys Ile Ile Ala Phe 1505 1510 1515 ggg gta ttg aac tac ttc aga gat gcc tgg aac gtc ttt gac ttt 4599 Gly Val Leu Asn Tyr Phe Arg Asp Ala Trp Asn Val Phe Asp Phe 1520 1525 1530 gtc acg gtt ttg gga agt att act gat att tta gta aca gag ata 4644 Val Thr Val Leu Gly Ser Ile Thr Asp Ile Leu Val Thr Glu Ile 1535 1540 1545 gcg aac aac ttc atc aac cta agc ttc ctt cgc ctc ttc cgg gcg 4689 Ala Asn Asn Phe Ile Asn Leu Ser Phe Leu Arg Leu Phe Arg Ala 1550 1555 1560 gca cgg ctg atc aag ctg ctt cgc cag ggc tac acc atc cgc atc 4734 Ala Arg Leu Ile Lys Leu Leu Arg Gln Gly Tyr Thr Ile Arg Ile 1565 1570 1575 cta ttg tgg acc ttc gtc cag tcc ttt aag gcg ctg ccc tac gtg 4779 Leu Leu Trp Thr Phe Val Gln Ser Phe Lys Ala Leu Pro Tyr Val 1580 1585 1590 tgc ctc ctc att gcc atg ctg ttc ttc atc tac gcc atc atc gga 4824 Cys Leu Leu Ile Ala Met Leu Phe Phe Ile Tyr Ala Ile Ile Gly 1595 1600 1605 atg cag gtt ttt gga aac att gcc ctt gat gat gac acc agt atc 4869 Met Gln Val Phe Gly Asn Ile Ala Leu Asp Asp Asp Thr Ser Ile 1610 1615 1620 aac cga cac aac aac ttc cgg aca ttt ctg caa gcc tta atg cta 4914 Asn Arg His Asn Asn Phe Arg Thr Phe Leu Gln Ala Leu Met Leu 1625 1630 1635 ttg ttc agg agt gcc act ggg gag gcc tgg cat gag atc atg ctg 4959 Leu Phe Arg Ser Ala Thr Gly Glu Ala Trp His Glu Ile Met Leu 1640 1645 1650 tct tgt ctg ggc aac cgg gcc tgt gac cca cat gcc aac gcc agt 5004 Ser Cys Leu Gly Asn Arg Ala Cys Asp Pro His Ala Asn Ala Ser 1655 1660 1665 gag tgc ggg agc gac ttt gcc tat ttt tat ttt gtc tcc ttc atc 5049 Glu Cys Gly Ser Asp Phe Ala Tyr Phe Tyr Phe Val Ser Phe Ile 1670 1675 1680 ttc ctc tgt tcc ttt ctg atg ttg aac ctc ttt gtt gct gta atc 5094 Phe Leu Cys Ser Phe Leu Met Leu Asn Leu Phe Val Ala Val Ile 1685 1690 1695 atg gac aat ttt gag tac ctc act cgg gac tct tcc atc cta ggg 5139 Met Asp Asn Phe Glu Tyr Leu Thr Arg Asp Ser Ser Ile Leu Gly 1700 1705 1710 cct cac cac tta gac gaa ttc att cga gtc tgg gct gaa tac gac 5184 Pro His His Leu Asp Glu Phe Ile Arg Val Trp Ala Glu Tyr Asp 1715 1720 1725 cca gct gcg tgt ggg cgc atc agt tac aat gac atg ttt gag atg 5229 Pro Ala Ala Cys Gly Arg Ile Ser Tyr Asn Asp Met Phe Glu Met 1730 1735 1740 ctg aaa cac atg tcc cca cct ctg ggg ttg ggg aag aaa tgc ccg 5274 Leu Lys His Met Ser Pro Pro Leu Gly Leu Gly Lys Lys Cys Pro 1745 1750 1755 gct cga gtt gca tac aag cgc ctg gtt cgc atg aac atg ccc ata 5319 Ala Arg Val Ala Tyr Lys Arg Leu Val Arg Met Asn Met Pro Ile 1760 1765 1770 tcc aat gag gac atg acg gtg cac ttt acg tcc aca ctg atg gcc 5364 Ser Asn Glu Asp Met Thr Val His Phe Thr Ser Thr Leu Met Ala 1775 1780 1785 ctc atc cgg aca gca ctg gag atc aag ctt gcc cca gcg ggg acg 5409 Leu Ile Arg Thr Ala Leu Glu Ile Lys Leu Ala Pro Ala Gly Thr 1790 1795 1800 aag cag cac cag tgt gat gct gag ctg aga aaa gag atc tct tct 5454 Lys Gln His Gln Cys Asp Ala Glu Leu Arg Lys Glu Ile Ser Ser 1805 1810 1815 gtg tgg gct aat ctg ccc cag aag act ctg gac tta ctg gta cca 5499 Val Trp Ala Asn Leu Pro Gln Lys Thr Leu Asp Leu Leu Val Pro 1820 1825 1830 ccc cac aaa cct gac gag atg aca gtg ggg aag gtc tat gct gct 5544 Pro His Lys Pro Asp Glu Met Thr Val Gly Lys Val Tyr Ala Ala 1835 1840 1845 ctc atg ata ttt gac ttc tac aaa cag aac aaa acc acc aga gat 5589 Leu Met Ile Phe Asp Phe Tyr Lys Gln Asn Lys Thr Thr Arg Asp 1850 1855 1860 cag act cac caa gct ccc gga ggc ctg tcc cag atg ggt ccc gtt 5634 Gln Thr His Gln Ala Pro Gly Gly Leu Ser Gln Met Gly Pro Val 1865 1870 1875 tcc ctg ttc cac cct ctg aag gcc acc ctg gaa cag aca cag ccc 5679 Ser Leu Phe His Pro Leu Lys Ala Thr Leu Glu Gln Thr Gln Pro 1880 1885 1890 gct gtg ctt cga gga gct cgg gtt ttc ctt cgg caa aag agt gca 5724 Ala Val Leu Arg Gly Ala Arg Val Phe Leu Arg Gln Lys Ser Ala 1895 1900 1905 act tcc ctc agc aat ggg ggt gcc ata caa acc cag gaa agt ggc 5769 Thr Ser Leu Ser Asn Gly Gly Ala Ile Gln Thr Gln Glu Ser Gly 1910 1915 1920 atc aag gag tcg ctg tcc tgg ggc acg cag agg acc caa gat gca 5814 Ile Lys Glu Ser Leu Ser Trp Gly Thr Gln Arg Thr Gln Asp Ala 1925 1930 1935 ctt tat gag gcc aga gca cct cta gaa cgt ggc cat tct gca gag 5859 Leu Tyr Glu Ala Arg Ala Pro Leu Glu Arg Gly His Ser Ala Glu 1940 1945 1950 atc cct gtg ggg cag tca gga aca ctg gct gtg gat gtc cag atg 5904 Ile Pro Val Gly Gln Ser Gly Thr Leu Ala Val Asp Val Gln Met 1955 1960 1965 cag aac atg aca ctg aga gga cca gat ggg gag ccc cag cct ggg 5949 Gln Asn Met Thr Leu Arg Gly Pro Asp Gly Glu Pro Gln Pro Gly 1970 1975 1980 ctg gaa agc caa ggc aga gct gcc tct atg cca cgc cta gcg gca 5994 Leu Glu Ser Gln Gly Arg Ala Ala Ser Met Pro Arg Leu Ala Ala 1985 1990 1995 gaa aca cag ccg gcc cct aat gcc agc ccc atg aag cgc tcc atc 6039 Glu Thr Gln Pro Ala Pro Asn Ala Ser Pro Met Lys Arg Ser Ile 2000 2005 2010 tcc aca ctg gct cca cgc cca cat ggg act cag ctt tgc agc aca 6084 Ser Thr Leu Ala Pro Arg Pro His Gly Thr Gln Leu Cys Ser Thr 2015 2020 2025 gtt ctg gac cgg cct cct cct agc cag gca tca cat cac cac cac 6129 Val Leu Asp Arg Pro Pro Pro Ser Gln Ala Ser His His His His 2030 2035 2040 cac cgc tgc cac cgg cgc aga gac aag aag caa agg tcc ctg gaa 6174 His Arg Cys His Arg Arg Arg Asp Lys Lys Gln Arg Ser Leu Glu 2045 2050 2055 aag ggg ccc agc ctg tct gtt gac cca gaa ggt gca cca agc act 6219 Lys Gly Pro Ser Leu Ser Val Asp Pro Glu Gly Ala Pro Ser Thr 2060 2065 2070 gct gca gga cct ggt ctg ccc cat gga gaa gga tcc acc gcc tgc 6264 Ala Ala Gly Pro Gly Leu Pro His Gly Glu Gly Ser Thr Ala Cys 2075 2080 2085 cgg cgg gac cgt aaa cag gag cga ggc cgg tcc cag gag cgg agg 6309 Arg Arg Asp Arg Lys Gln Glu Arg Gly Arg Ser Gln Glu Arg Arg 2090 2095 2100 cag ccc tca tct tcc tct tca gag aag cag cgc ttc tat tcc tgt 6354 Gln Pro Ser Ser Ser Ser Ser Glu Lys Gln Arg Phe Tyr Ser Cys 2105 2110 2115 gac cgc ttt ggg agc cgg gag ccc ccg caa ctg atg ccc tca ctc 6399 Asp Arg Phe Gly Ser Arg Glu Pro Pro Gln Leu Met Pro Ser Leu 2120 2125 2130 agt agc cac ccc aca tcg cca aca gcg gcg cta gag cca gca ccc 6444 Ser Ser His Pro Thr Ser Pro Thr Ala Ala Leu Glu Pro Ala Pro 2135 2140 2145 cac cca cag ggc agt ggt tcc gtt aat ggg agc ccc ttg atg tca 6489 His Pro Gln Gly Ser Gly Ser Val Asn Gly Ser Pro Leu Met Ser 2150 2155 2160 aca tcc ggt gct agc acc ccg ggc cga ggt ggg cgg agg cag ctc 6534 Thr Ser Gly Ala Ser Thr Pro Gly Arg Gly Gly Arg Arg Gln Leu 2165 2170 2175 ccc cag act cct ctg acc cca cgc ccc agc atc acc tac aag acc 6579 Pro Gln Thr Pro Leu Thr Pro Arg Pro Ser Ile Thr Tyr Lys Thr 2180 2185 2190 gcc aat tcc tcg cct gtc cac ttt gct gag ggt cag agc ggc ctc 6624 Ala Asn Ser Ser Pro Val His Phe Ala Glu Gly Gln Ser Gly Leu 2195 2200 2205 cca gcc ttc tcc cct ggc cgt ctc agc cgc ggc ctt tct gaa cac 6669 Pro Ala Phe Ser Pro Gly Arg Leu Ser Arg Gly Leu Ser Glu His 2210 2215 2220 aat gcc ctg ctc cag aaa gag ccc ctg agc cag cct cta gct cct 6714 Asn Ala Leu Leu Gln Lys Glu Pro Leu Ser Gln Pro Leu Ala Pro 2225 2230 2235 ggc tcc cga att ggc tct gac cct tac cta ggg cag cgt ctg gac 6759 Gly Ser Arg Ile Gly Ser Asp Pro Tyr Leu Gly Gln Arg Leu Asp 2240 2245 2250 agt gag gcc tcc gcc cac acc ctg cct gag gat aca ctc acc ttt 6804 Ser Glu Ala Ser Ala His Thr Leu Pro Glu Asp Thr Leu Thr Phe 2255 2260 2265 gaa gag gca gtg gcc acc aac tct ggc cgc tcc tcc agg act tcc 6849 Glu Glu Ala Val Ala Thr Asn Ser Gly Arg Ser Ser Arg Thr Ser 2270 2275 2280 tat gtg tcc tcc ctc act tcc caa tcc cac cct ctc cgc cgt gta 6894 Tyr Val Ser Ser Leu Thr Ser Gln Ser His Pro Leu Arg Arg Val 2285 2290 2295 ccc aat ggc tat cac tgc act ttg gga ctc agc act ggc gtc cgg 6939 Pro Asn Gly Tyr His Cys Thr Leu Gly Leu Ser Thr Gly Val Arg 2300 2305 2310 gcg cgg cac agc tac cac cac ccc gat cag gac cac tgg tgc tag 6984 Ala Arg His Ser Tyr His His Pro Asp Gln Asp His Trp Cys 2315 2320 2325 38 2327 PRT Mus musculus 38 Met Val Arg Phe Gly Asp Glu Leu Gly Gly Arg Tyr Gly Gly Thr Gly 1 5 10 15 Gly Gly Glu Arg Ala Arg Gly Gly Gly Ala Gly Gly Ala Gly Gly Pro 20 25 30 Gly Gln Gly Gly Leu Pro Pro Gly Gln Arg Val Leu Tyr Lys Gln Ser 35 40 45 Ile Ala Gln Arg Ala Arg Thr Met Ala Leu Tyr Asn Pro Ile Pro Val 50 55 60 Lys Gln Asn Cys Phe Thr Val Asn Arg Ser Leu Phe Val Phe Ser Glu 65 70 75 80 Asp Asn Val Val Arg Lys Tyr Ala Lys Arg Ile Thr Glu Trp Pro Pro 85 90 95 Phe Glu Tyr Met Ile Leu Ala Thr Ile Ile Ala Asn Cys Ile Val Leu 100 105 110 Ala Leu Glu Gln His Leu Pro Asp Gly Asp Lys Thr Pro Met Ser Glu 115 120 125 Arg Leu Asp Asp Thr Glu Pro Tyr Phe Ile Gly Ile Phe Cys Phe Glu 130 135 140 Ala Gly Ile Lys Ile Ile Ala Leu Gly Phe Val Phe His Lys Gly Ser 145 150 155 160 Tyr Leu Arg Asn Gly Trp Asn Val Met Asp Phe Val Val Val Leu Thr 165 170 175 Gly Ile Leu Ala Thr Ala Gly Thr Asp Phe Asp Leu Arg Thr Leu Arg 180 185 190 Ala Val Arg Val Leu Arg Pro Leu Lys Leu Val Ser Gly Ile Pro Ser 195 200 205 Leu Gln Val Val Leu Lys Ser Ile Met Lys Ala Met Val Pro Leu Leu 210 215 220 Gln Ile Gly Leu Leu Leu Phe Phe Ala Ile Leu Met Phe Ala Ile Ile 225 230 235 240 Gly Leu Glu Phe Tyr Met Gly Lys Phe His Lys Ala Cys Phe Pro Asn 245 250 255 Ser Thr Asp Thr Glu Pro Val Gly Asp Phe Pro Cys Gly Lys Asp Pro 260 265 270 Pro Ala Arg Gln Cys Asp Gly Asp Thr Glu Cys Arg Glu Tyr Trp Pro 275 280 285 Gly Pro Asn Phe Gly Ile Thr Asn Phe Asp Asn Ile Leu Phe Ala Ile 290 295 300 Leu Thr Val Phe Gln Cys Ile Thr Met Glu Gly Trp Thr Asp Ile Leu 305 310 315 320 Tyr Asn Thr Asn Asp Ala Ala Gly Asn Thr Trp Asn Trp Leu Tyr Phe 325 330 335 Ile Pro Leu Ile Ile Ile Gly Ser Phe Phe Met Leu Asn Leu Val Leu 340 345 350 Gly Val Leu Ser Gly Glu Phe Ala Lys Glu Arg Glu Arg Val Glu Asn 355 360 365 Arg Arg Ala Phe Leu Lys Leu Arg Arg Gln Gln Gln Ile Glu Arg Glu 370 375 380 Leu Asn Gly Tyr Leu Glu Trp Ile Phe Lys Ala Glu Glu Val Met Leu 385 390 395 400 Ala Glu Glu Asp Lys Asn Ala Glu Glu Lys Ser Pro Leu Asp Val Leu 405 410 415 Lys Arg Ala Ala Thr Lys Lys Ser Arg Asn Asp Leu Ile His Ala Glu 420 425 430 Glu Gly Glu Asp Arg Phe Val Asp Leu Cys Ala Val Gly Ser Pro Phe 435 440 445 Ala Arg Ala Ser Leu Lys Ser Gly Lys Thr Glu Ser Ser Ser Tyr Phe 450 455 460 Arg Arg Lys Glu Lys Met Phe Arg Phe Phe Ile Arg Arg Met Val Lys 465 470 475 480 Ala Gln Ser Phe Tyr Trp Val Val Leu Cys Val Val Ala Leu Asn Thr 485 490 495 Leu Cys Val Ala Met Val His Tyr Asn Gln Pro Gln Arg Leu Thr Thr 500 505 510 Ala Leu Tyr Phe Ala Glu Phe Val Phe Leu Gly Leu Phe Leu Thr Glu 515 520 525 Met Ser Leu Lys Met Tyr Gly Leu Gly Pro Arg Ser Tyr Phe Arg Ser 530 535 540 Ser Phe Asn Cys Phe Asp Phe Gly Val Ile Val Gly Ser Ile Phe Glu 545 550 555 560 Val Val Trp Ala Ala Ile Lys Pro Gly Thr Ser Phe Gly Ile Ser Val 565 570 575 Leu Arg Ala Leu Arg Leu Leu Arg Ile Phe Lys Val Thr Lys Tyr Trp 580 585 590 Asn Ser Leu Arg Asn Leu Val Val Ser Leu Leu Asn Ser Met Lys Ser 595 600 605 Ile Ile Ser Leu Leu Phe Leu Leu Phe Leu Phe Ile Val Val Phe Ala 610 615 620 Leu Leu Gly Met Gln Leu Phe Gly Gly Gln Phe Asn Phe Gln Asp Glu 625 630 635 640 Thr Pro Thr Thr Asn Phe Asp Thr Phe Pro Ala Ala Ile Leu Thr Val 645 650 655 Phe Gln Ile Leu Thr Gly Glu Asp Trp Asn Ala Val Met Tyr His Gly 660 665 670 Ile Glu Ser Gln Gly Gly Val Ser Lys Gly Met Phe Ser Ser Phe Tyr 675 680 685 Phe Ile Val Leu Thr Leu Phe Gly Asn Tyr Thr Leu Leu Asn Val Phe 690 695 700 Leu Ala Ile Ala Val Asp Asn Leu Ala Asn Ala Gln Glu Leu Thr Lys 705 710 715 720 Asp Glu Glu Glu Met Glu Glu Ala Ala Asn Gln Lys Leu Ala Leu Gln 725 730 735 Lys Ala Lys Glu Val Ala Glu Val Ser Pro Met Ser Ala Ala Asn Ile 740 745 750 Ser Ile Ala Ala Arg Gln Gln Asn Ser Ala Lys Ala Arg Ser Val Trp 755 760 765 Glu Gln Arg Ala Ser Gln Leu Arg Leu Gln Asn Leu Arg Ala Ser Cys 770 775 780 Glu Ala Leu Tyr Ser Glu Met Asp Pro Glu Glu Arg Leu Arg Tyr Ala 785 790 795 800 Ser Thr Arg His Val Arg Pro Asp Met Lys Thr His Met Asp Arg Pro 805 810 815 Leu Val Val Glu Pro Gly Arg Asp Gly Leu Arg Gly Pro Val Gly Ser 820 825 830 Lys Ser Lys Pro Glu Gly Thr Glu Ala Thr Glu Ser Ala Asp Leu Pro 835 840 845 Arg Arg His His Arg His Arg Asp Arg Asp Lys Thr Ser Ala Thr Ala 850 855 860 Pro Ala Gly Gly Glu Gln Asp Arg Thr Glu Ser Thr Glu Thr Gly Ala 865 870 875 880 Arg Glu Glu Arg Ala Arg Pro Arg Arg Ser His Ser Lys Glu Thr Pro 885 890 895 Gly Ala Asp Thr Gln Val Arg Cys Glu Arg Ser Arg Arg His His Arg 900 905 910 Arg Gly Ser Pro Glu Glu Ala Thr Glu Arg Glu Pro Arg Arg His Arg 915 920 925 Ala His Arg His Ala Gln Asp Ser Ser Lys Glu Gly Thr Ala Pro Val 930 935 940 Leu Val Pro Lys Gly Glu Arg Arg Ala Arg His Arg Gly Pro Arg Thr 945 950 955 960 Gly Pro Arg Glu Ala Glu Asn Asn Glu Glu Pro Thr Arg Arg His Arg 965 970 975 Ala Arg His Lys Val Pro Pro Thr Leu Gln Pro Pro Glu Arg Glu Ala 980 985 990 Ala Glu Lys Glu Ser Asn Ala Val Glu Gly Asp Lys Glu Thr Arg Asn 995 1000 1005 His Gln Pro Lys Glu Pro His Cys Asp Leu Glu Ala Ile Ala Val 1010 1015 1020 Thr Gly Val Gly Pro Leu His Met Leu Pro Ser Thr Cys Leu Gln 1025 1030 1035 Lys Val Asp Glu Gln Pro Glu Asp Ala Asp Asn Gln Arg Asn Val 1040 1045 1050 Thr Arg Met Gly Ser Gln Pro Ser Asp Pro Ser Thr Thr Val His 1055 1060 1065 Val Pro Val Thr Leu Thr Gly Pro Pro Gly Glu Thr Pro Val Val 1070 1075 1080 Pro Ser Gly Asn Met Asn Leu Glu Gly Gln Ala Glu Gly Lys Lys 1085 1090 1095 Glu Ala Glu Ala Asp Asp Val Leu Arg Arg Gly Pro Arg Pro Ile 1100 1105 1110 Val Pro Tyr Ser Ser Met Phe Cys Leu Ser Pro Thr Asn Leu Leu 1115 1120 1125 Arg Arg Phe Cys His Tyr Ile Val Thr Met Arg Tyr Phe Glu Met 1130 1135 1140 Val Ile Leu Val Val Ile Ala Leu Ser Ser Ile Ala Leu Ala Ala 1145 1150 1155 Glu Asp Pro Val Arg Thr Asp Ser Phe Arg Asn Asn Ala Leu Lys 1160 1165 1170 Tyr Met Asp Tyr Ile Phe Thr Gly Val Phe Thr Phe Glu Met Val 1175 1180 1185 Ile Lys Met Ile Asp Leu Gly Leu Leu Leu His Pro Gly Ala Tyr 1190 1195 1200 Phe Arg Asp Leu Trp Asn Ile Leu Asp Phe Ile Val Val Ser Gly 1205 1210 1215 Ala Leu Val Ala Phe Ala Phe Ser Ser Phe Met Gly Gly Ser Lys 1220 1225 1230 Gly Lys Asp Ile Asn Thr Ile Lys Ser Leu Arg Val Leu Arg Val 1235 1240 1245 Leu Arg Pro Leu Lys Thr Ile Lys Arg Leu Pro Lys Leu Lys Ala 1250 1255 1260 Val Phe Asp Cys Val Val Asn Ser Leu Lys Asn Val Leu Asn Ile 1265 1270 1275 Leu Ile Val Tyr Met Leu Phe Met Phe Ile Phe Ala Val Ile Ala 1280 1285 1290 Val Gln Leu Phe Lys Gly Lys Phe Phe Tyr Cys Thr Asp Glu Ser 1295 1300 1305 Lys Glu Leu Glu Arg Asp Cys Arg Gly Gln Tyr Leu Asp Tyr Glu 1310 1315 1320 Lys Glu Glu Val Glu Ala Gln Pro Arg Gln Trp Lys Lys Tyr Asp 1325 1330 1335 Phe His Tyr Asp Asn Val Leu Trp Ala Leu Leu Thr Leu Phe Thr 1340 1345 1350 Val Ser Thr Gly Glu Gly Trp Pro Met Val Leu Lys His Ser Val 1355 1360 1365 Asp Ala Thr Tyr Glu Glu Gln Gly Pro Ser Pro Gly Phe Arg Met 1370 1375 1380 Glu Leu Ser Ile Phe Tyr Val Val Tyr Phe Val Val Phe Pro Phe 1385 1390 1395 Phe Phe Val Asn Ile Phe Val Ala Leu Ile Ile Ile Thr Phe Gln 1400 1405 1410 Glu Gln Gly Asp Lys Val Met Ser Glu Cys Ser Leu Glu Lys Asn 1415 1420 1425 Glu Arg Ala Cys Ile Asp Phe Ala Ile Ser Ala Lys Pro Leu Thr 1430 1435 1440 Arg Tyr Met Pro Gln Asn Lys Gln Ser Phe Gln Tyr Lys Thr Trp 1445 1450 1455 Thr Phe Val Val Ser Pro Pro Phe Glu Tyr Phe Ile Met Ala Met 1460 1465 1470 Ile Ala Leu Asn Thr Val Val Leu Met Met Lys Phe Tyr Asp Ala 1475 1480 1485 Pro Tyr Glu Tyr Glu Leu Met Leu Lys Cys Leu Asn Ile Val Phe 1490 1495 1500 Thr Ser Met Phe Ser Met Glu Cys Ile Leu Lys Ile Ile Ala Phe 1505 1510 1515 Gly Val Leu Asn Tyr Phe Arg Asp Ala Trp Asn Val Phe Asp Phe 1520 1525 1530 Val Thr Val Leu Gly Ser Ile Thr Asp Ile Leu Val Thr Glu Ile 1535 1540 1545 Ala Asn Asn Phe Ile Asn Leu Ser Phe Leu Arg Leu Phe Arg Ala 1550 1555 1560 Ala Arg Leu Ile Lys Leu Leu Arg Gln Gly Tyr Thr Ile Arg Ile 1565 1570 1575 Leu Leu Trp Thr Phe Val Gln Ser Phe Lys Ala Leu Pro Tyr Val 1580 1585 1590 Cys Leu Leu Ile Ala Met Leu Phe Phe Ile Tyr Ala Ile Ile Gly 1595 1600 1605 Met Gln Val Phe Gly Asn Ile Ala Leu Asp Asp Asp Thr Ser Ile 1610 1615 1620 Asn Arg His Asn Asn Phe Arg Thr Phe Leu Gln Ala Leu Met Leu 1625 1630 1635 Leu Phe Arg Ser Ala Thr Gly Glu Ala Trp His Glu Ile Met Leu 1640 1645 1650 Ser Cys Leu Gly Asn Arg Ala Cys Asp Pro His Ala Asn Ala Ser 1655 1660 1665 Glu Cys Gly Ser Asp Phe Ala Tyr Phe Tyr Phe Val Ser Phe Ile 1670 1675 1680 Phe Leu Cys Ser Phe Leu Met Leu Asn Leu Phe Val Ala Val Ile 1685 1690 1695 Met Asp Asn Phe Glu Tyr Leu Thr Arg Asp Ser Ser Ile Leu Gly 1700 1705 1710 Pro His His Leu Asp Glu Phe Ile Arg Val Trp Ala Glu Tyr Asp 1715 1720 1725 Pro Ala Ala Cys Gly Arg Ile Ser Tyr Asn Asp Met Phe Glu Met 1730 1735 1740 Leu Lys His Met Ser Pro Pro Leu Gly Leu Gly Lys Lys Cys Pro 1745 1750 1755 Ala Arg Val Ala Tyr Lys Arg Leu Val Arg Met Asn Met Pro Ile 1760 1765 1770 Ser Asn Glu Asp Met Thr Val His Phe Thr Ser Thr Leu Met Ala 1775 1780 1785 Leu Ile Arg Thr Ala Leu Glu Ile Lys Leu Ala Pro Ala Gly Thr 1790 1795 1800 Lys Gln His Gln Cys Asp Ala Glu Leu Arg Lys Glu Ile Ser Ser 1805 1810 1815 Val Trp Ala Asn Leu Pro Gln Lys Thr Leu Asp Leu Leu Val Pro 1820 1825 1830 Pro His Lys Pro Asp Glu Met Thr Val Gly Lys Val Tyr Ala Ala 1835 1840 1845 Leu Met Ile Phe Asp Phe Tyr Lys Gln Asn Lys Thr Thr Arg Asp 1850 1855 1860 Gln Thr His Gln Ala Pro Gly Gly Leu Ser Gln Met Gly Pro Val 1865 1870 1875 Ser Leu Phe His Pro Leu Lys Ala Thr Leu Glu Gln Thr Gln Pro 1880 1885 1890 Ala Val Leu Arg Gly Ala Arg Val Phe Leu Arg Gln Lys Ser Ala 1895 1900 1905 Thr Ser Leu Ser Asn Gly Gly Ala Ile Gln Thr Gln Glu Ser Gly 1910 1915 1920 Ile Lys Glu Ser Leu Ser Trp Gly Thr Gln Arg Thr Gln Asp Ala 1925 1930 1935 Leu Tyr Glu Ala Arg Ala Pro Leu Glu Arg Gly His Ser Ala Glu 1940 1945 1950 Ile Pro Val Gly Gln Ser Gly Thr Leu Ala Val Asp Val Gln Met 1955 1960 1965 Gln Asn Met Thr Leu Arg Gly Pro Asp Gly Glu Pro Gln Pro Gly 1970 1975 1980 Leu Glu Ser Gln Gly Arg Ala Ala Ser Met Pro Arg Leu Ala Ala 1985 1990 1995 Glu Thr Gln Pro Ala Pro Asn Ala Ser Pro Met Lys Arg Ser Ile 2000 2005 2010 Ser Thr Leu Ala Pro Arg Pro His Gly Thr Gln Leu Cys Ser Thr 2015 2020 2025 Val Leu Asp Arg Pro Pro Pro Ser Gln Ala Ser His His His His 2030 2035 2040 His Arg Cys His Arg Arg Arg Asp Lys Lys Gln Arg Ser Leu Glu 2045 2050 2055 Lys Gly Pro Ser Leu Ser Val Asp Pro Glu Gly Ala Pro Ser Thr 2060 2065 2070 Ala Ala Gly Pro Gly Leu Pro His Gly Glu Gly Ser Thr Ala Cys 2075 2080 2085 Arg Arg Asp Arg Lys Gln Glu Arg Gly Arg Ser Gln Glu Arg Arg 2090 2095 2100 Gln Pro Ser Ser Ser Ser Ser Glu Lys Gln Arg Phe Tyr Ser Cys 2105 2110 2115 Asp Arg Phe Gly Ser Arg Glu Pro Pro Gln Leu Met Pro Ser Leu 2120 2125 2130 Ser Ser His Pro Thr Ser Pro Thr Ala Ala Leu Glu Pro Ala Pro 2135 2140 2145 His Pro Gln Gly Ser Gly Ser Val Asn Gly Ser Pro Leu Met Ser 2150 2155 2160 Thr Ser Gly Ala Ser Thr Pro Gly Arg Gly Gly Arg Arg Gln Leu 2165 2170 2175 Pro Gln Thr Pro Leu Thr Pro Arg Pro Ser Ile Thr Tyr Lys Thr 2180 2185 2190 Ala Asn Ser Ser Pro Val His Phe Ala Glu Gly Gln Ser Gly Leu 2195 2200 2205 Pro Ala Phe Ser Pro Gly Arg Leu Ser Arg Gly Leu Ser Glu His 2210 2215 2220 Asn Ala Leu Leu Gln Lys Glu Pro Leu Ser Gln Pro Leu Ala Pro 2225 2230 2235 Gly Ser Arg Ile Gly Ser Asp Pro Tyr Leu Gly Gln Arg Leu Asp 2240 2245 2250 Ser Glu Ala Ser Ala His Thr Leu Pro Glu Asp Thr Leu Thr Phe 2255 2260 2265 Glu Glu Ala Val Ala Thr Asn Ser Gly Arg Ser Ser Arg Thr Ser 2270 2275 2280 Tyr Val Ser Ser Leu Thr Ser Gln Ser His Pro Leu Arg Arg Val 2285 2290 2295 Pro Asn Gly Tyr His Cys Thr Leu Gly Leu Ser Thr Gly Val Arg 2300 2305 2310 Ala Arg His Ser Tyr His His Pro Asp Gln Asp His Trp Cys 2315 2320 2325 39 7185 DNA Mus musculus CDS (121)..(6987) 39 ggaattcggc tcgaggggcg aggtccaggc agctcgctgc ggctaggcta ggagcccttg 60 gcgcgccgcg ccctcggtgc cgggccgcgg agcccgggat gctcgcggcg cccgggagtc 120 atg gtc cgc ttc ggg gac gag cta ggc ggc cgc tat ggg ggc acc ggc 168 Met Val Arg Phe Gly Asp Glu Leu Gly Gly Arg Tyr Gly Gly Thr Gly 1 5 10 15 ggc ggg gag cgg gct cgg ggc ggc ggg gcc ggc ggg gcg ggt ggc ccg 216 Gly Gly Glu Arg Ala Arg Gly Gly Gly Ala Gly Gly Ala Gly Gly Pro 20 25 30 ggc cag ggg ggt ctg ccg ccg ggc cag cgg gtc ctg tac aag cag tcc 264 Gly Gln Gly Gly Leu Pro Pro Gly Gln Arg Val Leu Tyr Lys Gln Ser 35 40 45 att gcg cag cgc gca cgg act atg gcc ctg tac aac ccc atc cca gtc 312 Ile Ala Gln Arg Ala Arg Thr Met Ala Leu Tyr Asn Pro Ile Pro Val 50 55 60 aag cag aac tgc ttc acc gtc aac cgc tcg ctc ttc gtc ttc agc gag 360 Lys Gln Asn Cys Phe Thr Val Asn Arg Ser Leu Phe Val Phe Ser Glu 65 70 75 80 gac aac gtc gtc cgc aaa tac gct aag cgc atc acc gaa tgg ccg ccc 408 Asp Asn Val Val Arg Lys Tyr Ala Lys Arg Ile Thr Glu Trp Pro Pro 85 90 95 ttc gaa tac atg atc ctg gcc acc atc atc gcc aac tgc att gtt ctg 456 Phe Glu Tyr Met Ile Leu Ala Thr Ile Ile Ala Asn Cys Ile Val Leu 100 105 110 gcc ctg gag cag cac ctc cct gat ggg gac aag act ccc atg tct gag 504 Ala Leu Glu Gln His Leu Pro Asp Gly Asp Lys Thr Pro Met Ser Glu 115 120 125 cga cta gat gac acg gag cct tac ttc atc ggg atc ttt tgc ttt gag 552 Arg Leu Asp Asp Thr Glu Pro Tyr Phe Ile Gly Ile Phe Cys Phe Glu 130 135 140 gcg ggc atc aag atc ata gcc ctg ggc ttt gtt ttc cac aag ggc tcc 600 Ala Gly Ile Lys Ile Ile Ala Leu Gly Phe Val Phe His Lys Gly Ser 145 150 155 160 tac ctt cgg aac ggc tgg aat gtc atg gac ttc gtg gtg gta ctc acg 648 Tyr Leu Arg Asn Gly Trp Asn Val Met Asp Phe Val Val Val Leu Thr 165 170 175 ggg att ctc gcc aca gct gga act gac ttt gac ctg cgc aca ctg agg 696 Gly Ile Leu Ala Thr Ala Gly Thr Asp Phe Asp Leu Arg Thr Leu Arg 180 185 190 gct gtg cgt gtg ctt agg ccc ctg aag ctg gtg tct gga att cca agc 744 Ala Val Arg Val Leu Arg Pro Leu Lys Leu Val Ser Gly Ile Pro Ser 195 200 205 ttg cag gtg gtg ctt aag tcc atc atg aag gcc atg gtc ccg ctg ctg 792 Leu Gln Val Val Leu Lys Ser Ile Met Lys Ala Met Val Pro Leu Leu 210 215 220 cag att ggg ctg ctg ctc ttc ttt gcc atc ctc atg ttt ggc atc atc 840 Gln Ile Gly Leu Leu Leu Phe Phe Ala Ile Leu Met Phe Gly Ile Ile 225 230 235 240 ggc ctc gag ttc tat atg ggc aaa ttc cat aag gcc tgt ttc ccc aac 888 Gly Leu Glu Phe Tyr Met Gly Lys Phe His Lys Ala Cys Phe Pro Asn 245 250 255 agc aca gat aca gag cct gtg ggt gac ttt ccc tgt ggc aaa gat ccc 936 Ser Thr Asp Thr Glu Pro Val Gly Asp Phe Pro Cys Gly Lys Asp Pro 260 265 270 cct gct cgt cag tgt gat ggt gac acc gaa tgc cgg gag tac tgg cca 984 Pro Ala Arg Gln Cys Asp Gly Asp Thr Glu Cys Arg Glu Tyr Trp Pro 275 280 285 gga ccc aac ttt ggt atc acc aat ttt gac aac atc ctg ttt gcc atc 1032 Gly Pro Asn Phe Gly Ile Thr Asn Phe Asp Asn Ile Leu Phe Ala Ile 290 295 300 ttg aca gtg ttc cag tgt atc acc atg gag ggc tgg act gac atc ctc 1080 Leu Thr Val Phe Gln Cys Ile Thr Met Glu Gly Trp Thr Asp Ile Leu 305 310 315 320 tac aat aca aat gat gcg gct ggc aac acg tgg aac tgg ttg tac ttc 1128 Tyr Asn Thr Asn Asp Ala Ala Gly Asn Thr Trp Asn Trp Leu Tyr Phe 325 330 335 atc ccc ctc atc atc att ggc tcc ttc ttc atg ctc aac ctg gtg ctg 1176 Ile Pro Leu Ile Ile Ile Gly Ser Phe Phe Met Leu Asn Leu Val Leu 340 345 350 ggt gtg ctt tct gga gag ttt gcc aag gag cgg gag cga gtc gag aac 1224 Gly Val Leu Ser Gly Glu Phe Ala Lys Glu Arg Glu Arg Val Glu Asn 355 360 365 cgc cga gcc ttc ctg aag ctc cgc agg cag cag cag att gag cga gag 1272 Arg Arg Ala Phe Leu Lys Leu Arg Arg Gln Gln Gln Ile Glu Arg Glu 370 375 380 ctg aat ggg tac ttg gag tgg atc ttc aag gca gag gaa gtc atg ttg 1320 Leu Asn Gly Tyr Leu Glu Trp Ile Phe Lys Ala Glu Glu Val Met Leu 385 390 395 400 gca gag gag gac aag aat gca gaa gag aaa tcc cct ttg gat gtg ttg 1368 Ala Glu Glu Asp Lys Asn Ala Glu Glu Lys Ser Pro Leu Asp Val Leu 405 410 415 aag aga gct gcc acc aag aag agc cga aat gac ctc atc cat gca gaa 1416 Lys Arg Ala Ala Thr Lys Lys Ser Arg Asn Asp Leu Ile His Ala Glu 420 425 430 gag ggg gag gac cgg ttt gta gac ctc tgt gca gtt ggg tct cca ttt 1464 Glu Gly Glu Asp Arg Phe Val Asp Leu Cys Ala Val Gly Ser Pro Phe 435 440 445 gct cgt gcc agc ctc aag agt ggg aag acg gag agc tca tcg tac ttc 1512 Ala Arg Ala Ser Leu Lys Ser Gly Lys Thr Glu Ser Ser Ser Tyr Phe 450 455 460 cgg aga aag gag aag atg ttc cgg ttc ttt atc cgg cgt atg gtg aaa 1560 Arg Arg Lys Glu Lys Met Phe Arg Phe Phe Ile Arg Arg Met Val Lys 465 470 475 480 gca cag agc ttc tac tgg gtg gta ctg tgt gtg gtg gcc ctg aac aca 1608 Ala Gln Ser Phe Tyr Trp Val Val Leu Cys Val Val Ala Leu Asn Thr 485 490 495 ctg tgt gtg gcc atg gtg cac tat aat cag cct cag cgg ctt acc act 1656 Leu Cys Val Ala Met Val His Tyr Asn Gln Pro Gln Arg Leu Thr Thr 500 505 510 gca ctg tac ttt gca gag ttt gtt ttc ctg ggt ctc ttc ctc aca gag 1704 Ala Leu Tyr Phe Ala Glu Phe Val Phe Leu Gly Leu Phe Leu Thr Glu 515 520 525 atg tcc ctg aag atg tat ggc cta ggg ccc aga agt tac ttc agg tct 1752 Met Ser Leu Lys Met Tyr Gly Leu Gly Pro Arg Ser Tyr Phe Arg Ser 530 535 540 tcc ttc aac tgc ttt gac ttt ggg gtg att gtg ggg agt atc ttt gaa 1800 Ser Phe Asn Cys Phe Asp Phe Gly Val Ile Val Gly Ser Ile Phe Glu 545 550 555 560 gta gtc tgg gct gcc atc aag cca gga acc tcc ttt gga atc agt gtg 1848 Val Val Trp Ala Ala Ile Lys Pro Gly Thr Ser Phe Gly Ile Ser Val 565 570 575 ctg cgg gct ctg cga ctg ctg agg ata ttc aaa gtt acc aag tat tgg 1896 Leu Arg Ala Leu Arg Leu Leu Arg Ile Phe Lys Val Thr Lys Tyr Trp 580 585 590 aac tct ctg agg aac ctg gtg gtt tcc ctc ctc aat tcc atg aag tcc 1944 Asn Ser Leu Arg Asn Leu Val Val Ser Leu Leu Asn Ser Met Lys Ser 595 600 605 atc atc agc ctt ctc ttc ctg ctt ttc ctc ttc atc gtg gtc ttc gct 1992 Ile Ile Ser Leu Leu Phe Leu Leu Phe Leu Phe Ile Val Val Phe Ala 610 615 620 ctg ttg ggg atg cag ctg ttc gga gga cag ttc aac ttt caa gat gag 2040 Leu Leu Gly Met Gln Leu Phe Gly Gly Gln Phe Asn Phe Gln Asp Glu 625 630 635 640 act cca acc acc att ttt gat acc ttc cca gct gcc atc ctc act gtc 2088 Thr Pro Thr Thr Ile Phe Asp Thr Phe Pro Ala Ala Ile Leu Thr Val 645 650 655 ttt cag atc ctg aca gga gag gat tgg aat gcc gta atg tat cat ggg 2136 Phe Gln Ile Leu Thr Gly Glu Asp Trp Asn Ala Val Met Tyr His Gly 660 665 670 att gag tca caa ggt gga gtc agc aaa ggc atg ttt tct tcc ttt tac 2184 Ile Glu Ser Gln Gly Gly Val Ser Lys Gly Met Phe Ser Ser Phe Tyr 675 680 685 ttc atc gtc ctg aca ctg ttt gga aac tac acc ctg ctg aat gtt ttt 2232 Phe Ile Val Leu Thr Leu Phe Gly Asn Tyr Thr Leu Leu Asn Val Phe 690 695 700 ctg gcc att gct gtg gac aac ctt gcc aat gcc cag gag ttg acc aag 2280 Leu Ala Ile Ala Val Asp Asn Leu Ala Asn Ala Gln Glu Leu Thr Lys 705 710 715 720 gat gaa gag gag atg gaa gaa gca gcc aat cag aaa ctt gct ctt cag 2328 Asp Glu Glu Glu Met Glu Glu Ala Ala Asn Gln Lys Leu Ala Leu Gln 725 730 735 aag gcc aaa gaa gta gct gaa gtc agc ccc atg tct gct gcc aat atc 2376 Lys Ala Lys Glu Val Ala Glu Val Ser Pro Met Ser Ala Ala Asn Ile 740 745 750 tcc atc gct gcg cag gag aac tcg gcc aag gcg cgc tca gta tgg gag 2424 Ser Ile Ala Ala Gln Glu Asn Ser Ala Lys Ala Arg Ser Val Trp Glu 755 760 765 cag cgg gcc agt cag cta agg ctc cag aat ctg cgt gcc agc tgt gag 2472 Gln Arg Ala Ser Gln Leu Arg Leu Gln Asn Leu Arg Ala Ser Cys Glu 770 775 780 gca ttg tac agt gag atg gac cct gag gag cgc ctg cgt tat gcc agc 2520 Ala Leu Tyr Ser Glu Met Asp Pro Glu Glu Arg Leu Arg Tyr Ala Ser 785 790 795 800 acg cgc cat gtg agg cca gac atg aag aca cac atg gac cga ccc cta 2568 Thr Arg His Val Arg Pro Asp Met Lys Thr His Met Asp Arg Pro Leu 805 810 815 gtg gtg gag cct ggt cga gat ggc ttg cgg gga ccc gtt ggg agc aag 2616 Val Val Glu Pro Gly Arg Asp Gly Leu Arg Gly Pro Val Gly Ser Lys 820 825 830 tca aag cct gaa ggc acg gag gcc aca gaa agc gcg gac cta cct cgc 2664 Ser Lys Pro Glu Gly Thr Glu Ala Thr Glu Ser Ala Asp Leu Pro Arg 835 840 845 cgg cac cac cgg cat cgt gat agg gac aag acc tca gcc aca gca cct 2712 Arg His His Arg His Arg Asp Arg Asp Lys Thr Ser Ala Thr Ala Pro 850 855 860 gct gga ggc gaa cag gac agg aca gaa agc acc gag acc ggg ccc cgg 2760 Ala Gly Gly Glu Gln Asp Arg Thr Glu Ser Thr Glu Thr Gly Pro Arg 865 870 875 880 gag gaa cgt gcg cgc cct cgt cga agt cac agc aag gag act cca ggg 2808 Glu Glu Arg Ala Arg Pro Arg Arg Ser His Ser Lys Glu Thr Pro Gly 885 890 895 gct gac acg caa gtg cgc tgt gag cgc agt agg cgt cac cac cgg cgc 2856 Ala Asp Thr Gln Val Arg Cys Glu Arg Ser Arg Arg His His Arg Arg 900 905 910 ggc tcc ccg gag gag gcc act gaa cgg gag cct cgg cgc cac cgt gcc 2904 Gly Ser Pro Glu Glu Ala Thr Glu Arg Glu Pro Arg Arg His Arg Ala 915 920 925 cac cgg cat gca cag gac tca agc aag gag ggc acg gcg ccg gtg ctt 2952 His Arg His Ala Gln Asp Ser Ser Lys Glu Gly Thr Ala Pro Val Leu 930 935 940 gta ccc aag ggt gag cga cga gca aga cac cga ggc cca cgc acg ggt 3000 Val Pro Lys Gly Glu Arg Arg Ala Arg His Arg Gly Pro Arg Thr Gly 945 950 955 960 cca cgt gag gca gag aac aac gag gag ccc aca cgc agg cac cgt gca 3048 Pro Arg Glu Ala Glu Asn Asn Glu Glu Pro Thr Arg Arg His Arg Ala 965 970 975 agg cat aag gtg cca ccc aca ctg cag ccc cca gag agg gag gct gca 3096 Arg His Lys Val Pro Pro Thr Leu Gln Pro Pro Glu Arg Glu Ala Ala 980 985 990 gag aag gag agc aac gcg gtg gaa ggg gat aag gaa acc cga aat cac 3144 Glu Lys Glu Ser Asn Ala Val Glu Gly Asp Lys Glu Thr Arg Asn His 995 1000 1005 cag ccc aag gaa cct cac tgt gac ctg gag gcc att gca gtt aca 3189 Gln Pro Lys Glu Pro His Cys Asp Leu Glu Ala Ile Ala Val Thr 1010 1015 1020 ggt gtg ggc cct ctg cac atg ctg ccc agc acc tgt ctc cag aaa 3234 Gly Val Gly Pro Leu His Met Leu Pro Ser Thr Cys Leu Gln Lys 1025 1030 1035 gtg gac gag caa cca gag gat gca gac aac cag cgt aat gtc acc 3279 Val Asp Glu Gln Pro Glu Asp Ala Asp Asn Gln Arg Asn Val Thr 1040 1045 1050 cgg atg ggc agt cag ccc tca gat ccc agc acc act gtg cat gtc 3324 Arg Met Gly Ser Gln Pro Ser Asp Pro Ser Thr Thr Val His Val 1055 1060 1065 cca gtg aca ctg aca ggc cct cct ggg gag acc cct gta gtt ccc 3369 Pro Val Thr Leu Thr Gly Pro Pro Gly Glu Thr Pro Val Val Pro 1070 1075 1080 agt ggt aac atg aac ctg gaa ggc caa gca gag ggc aag aag gag 3414 Ser Gly Asn Met Asn Leu Glu Gly Gln Ala Glu Gly Lys Lys Glu 1085 1090 1095 gca gag gcg gat gat gtg ctg aga aga ggc ccc agg ccc atc gtt 3459 Ala Glu Ala Asp Asp Val Leu Arg Arg Gly Pro Arg Pro Ile Val 1100 1105 1110 ccc tac agc tcc atg ttt tgt ctc agc ccc acc aac ctg ttt cgt 3504 Pro Tyr Ser Ser Met Phe Cys Leu Ser Pro Thr Asn Leu Phe Arg 1115 1120 1125 cgc ttc tgc cat tac att gtg acc atg cgg tac ttg gag atg gta 3549 Arg Phe Cys His Tyr Ile Val Thr Met Arg Tyr Leu Glu Met Val 1130 1135 1140 att ctt gtg gtc att gcc ttg agc agc att gcc ctg gct gca gag 3594 Ile Leu Val Val Ile Ala Leu Ser Ser Ile Ala Leu Ala Ala Glu 1145 1150 1155 gat cct gtg cgg aca gat tca ttc agg aac aac gct tta gag tac 3639 Asp Pro Val Arg Thr Asp Ser Phe Arg Asn Asn Ala Leu Glu Tyr 1160 1165 1170 atg gat tac atc ttt aca gga gtc ttc acc tgt gaa atg gtc ata 3684 Met Asp Tyr Ile Phe Thr Gly Val Phe Thr Cys Glu Met Val Ile 1175 1180 1185 aag atg ata gac ttg ggc ttg ctg ctg cac cct ggt gcc tac ttc 3729 Lys Met Ile Asp Leu Gly Leu Leu Leu His Pro Gly Ala Tyr Phe 1190 1195 1200 cgg gac ctg tgg aac att ctg gac ttc atc gtt gtc agt gga gcc 3774 Arg Asp Leu Trp Asn Ile Leu Asp Phe Ile Val Val Ser Gly Ala 1205 1210 1215 ctg gtg gca ttt gcg ttc tca gga tcc aaa ggg aaa gac atc aat 3819 Leu Val Ala Phe Ala Phe Ser Gly Ser Lys Gly Lys Asp Ile Asn 1220 1225 1230 acc atc aag tct ctg aga gtc ctg cgt gtc ctg agg ccc ctc aag 3864 Thr Ile Lys Ser Leu Arg Val Leu Arg Val Leu Arg Pro Leu Lys 1235 1240 1245 acc atc aag cgg ctg cct aaa ctc aag gct gtc ttt gac tgt gtg 3909 Thr Ile Lys Arg Leu Pro Lys Leu Lys Ala Val Phe Asp Cys Val 1250 1255 1260 gtg aac tcc ctg aag aac gtc ttg aac atc ctg att gtc tac atg 3954 Val Asn Ser Leu Lys Asn Val Leu Asn Ile Leu Ile Val Tyr Met 1265 1270 1275 ctc ttc atg ttc ata ttt gcc gtc att gcc gtc cag ctc ttc aaa 3999 Leu Phe Met Phe Ile Phe Ala Val Ile Ala Val Gln Leu Phe Lys 1280 1285 1290 ggg aag ttc ttt tac tgt act gat gaa tcc aag gag ctg gag agg 4044 Gly Lys Phe Phe Tyr Cys Thr Asp Glu Ser Lys Glu Leu Glu Arg 1295 1300 1305 gac tgc cgg ggt cag tat ttg gat tat gag aag gaa gaa gta gaa 4089 Asp Cys Arg Gly Gln Tyr Leu Asp Tyr Glu Lys Glu Glu Val Glu 1310 1315 1320 gcc cag cca agg cag tgg aag aaa tat gac ttc cac tat gac aat 4134 Ala Gln Pro Arg Gln Trp Lys Lys Tyr Asp Phe His Tyr Asp Asn 1325 1330 1335 gtt ctc tgg gcc ttg ttg acg ctg ttc aca gtg tcc acg gga gag 4179 Val Leu Trp Ala Leu Leu Thr Leu Phe Thr Val Ser Thr Gly Glu 1340 1345 1350 ggg tgg ccc atg gtg ctg aaa cac tct gtg gat gcc acc tat gag 4224 Gly Trp Pro Met Val Leu Lys His Ser Val Asp Ala Thr Tyr Glu 1355 1360 1365 gaa cag ggg ccc agt ccc ggc ttc cgg atg gag ctc tcc atc ctc 4269 Glu Gln Gly Pro Ser Pro Gly Phe Arg Met Glu Leu Ser Ile Leu 1370 1375 1380 tac gtg gtc tac ttt gtg gtc ttc cct ttt ttc ttt gtc aac atc 4314 Tyr Val Val Tyr Phe Val Val Phe Pro Phe Phe Phe Val Asn Ile 1385 1390 1395 ttt gtg gcc ttg atc att atc acc ttc cag gaa cag gga gat aag 4359 Phe Val Ala Leu Ile Ile Ile Thr Phe Gln Glu Gln Gly Asp Lys 1400 1405 1410 gtg atg tct gaa tgc agc tta gaa aag aat gag agg gct tgc att 4404 Val Met Ser Glu Cys Ser Leu Glu Lys Asn Glu Arg Ala Cys Ile 1415 1420 1425 gat ttt gcc atc agt gcc aag ccc ctg aca cgg tac atg cct caa 4449 Asp Phe Ala Ile Ser Ala Lys Pro Leu Thr Arg Tyr Met Pro Gln 1430 1435 1440 aac aaa cag tcg ttc cag tat aag aca tgg aca ttc gtg gtc tct 4494 Asn Lys Gln Ser Phe Gln Tyr Lys Thr Trp Thr Phe Val Val Ser 1445 1450 1455 cca ccc ttt gag tac ttc atc atg gct atg ata gcc ctc aac aca 4539 Pro Pro Phe Glu Tyr Phe Ile Met Ala Met Ile Ala Leu Asn Thr 1460 1465 1470 gtg gtg ctg atg atg aag ttc tat gat gca cct tat gag tac gag 4584 Val Val Leu Met Met Lys Phe Tyr Asp Ala Pro Tyr Glu Tyr Glu 1475 1480 1485 ctg atg ctg aaa tgc ctg aac att gtc ttc aca tcc atg ttc tcg 4629 Leu Met Leu Lys Cys Leu Asn Ile Val Phe Thr Ser Met Phe Ser 1490 1495 1500 atg gag tgc ata ctg aag atc atc gcc ttt ggg gta ttg aac tac 4674 Met Glu Cys Ile Leu Lys Ile Ile Ala Phe Gly Val Leu Asn Tyr 1505 1510 1515 ttc aga gat gcc tgg aat gtc ttt gac ttt gtc acg gtt ttg gga 4719 Phe Arg Asp Ala Trp Asn Val Phe Asp Phe Val Thr Val Leu Gly 1520 1525 1530 agt att act gat att tta gta aca gag att gcg gaa acg aac aac 4764 Ser Ile Thr Asp Ile Leu Val Thr Glu Ile Ala Glu Thr Asn Asn 1535 1540 1545 ttc atc aac cta agc ttc ctt cgc ctc ttc cgg gcg gca cgg ctg 4809 Phe Ile Asn Leu Ser Phe Leu Arg Leu Phe Arg Ala Ala Arg Leu 1550 1555 1560 atc aag ctg ctt cgc cag ggc tac acc atc cgc atc cta ttg tgg 4854 Ile Lys Leu Leu Arg Gln Gly Tyr Thr Ile Arg Ile Leu Leu Trp 1565 1570 1575 acc ttc gtc cag tcc ttt aag gcg ctg ccc tac gtg tgc ctc ctc 4899 Thr Phe Val Gln Ser Phe Lys Ala Leu Pro Tyr Val Cys Leu Leu 1580 1585 1590 att gcc atg ctg ttc ttc atc tac gcc atc atc gga atg cag gtt 4944 Ile Ala Met Leu Phe Phe Ile Tyr Ala Ile Ile Gly Met Gln Val 1595 1600 1605 ttt gga aac agt gcc ctt gat gat gac acc agt atc aac cga cac 4989 Phe Gly Asn Ser Ala Leu Asp Asp Asp Thr Ser Ile Asn Arg His 1610 1615 1620 aac aac ttc cgg aca ttt ctg caa gcc ata atg cta ttg ttc agg 5034 Asn Asn Phe Arg Thr Phe Leu Gln Ala Ile Met Leu Leu Phe Arg 1625 1630 1635 agt gcc act ggg gag gcc tgg cat gag atc atg ctg tca tgt ctg 5079 Ser Ala Thr Gly Glu Ala Trp His Glu Ile Met Leu Ser Cys Leu 1640 1645 1650 gac aac cgg gcc tgt gac cca cat gcc aac gcc agt gag tgc ggg 5124 Asp Asn Arg Ala Cys Asp Pro His Ala Asn Ala Ser Glu Cys Gly 1655 1660 1665 agc gac ttt gcc tat ttt tat ttt gtc tcc ttc atc ttc ctc tgt 5169 Ser Asp Phe Ala Tyr Phe Tyr Phe Val Ser Phe Ile Phe Leu Cys 1670 1675 1680 tcc ttt ctg atg ttg aac ctc ttt gtt gct gta atc atg gac aat 5214 Ser Phe Leu Met Leu Asn Leu Phe Val Ala Val Ile Met Asp Asn 1685 1690 1695 ttt gag tac ctc act cgg gac tct tcc atc cta ggg cct cac cac 5259 Phe Glu Tyr Leu Thr Arg Asp Ser Ser Ile Leu Gly Pro His His 1700 1705 1710 tta gac gaa ttc att cga gtc tgg gct gaa tac gac cca gct gcg 5304 Leu Asp Glu Phe Ile Arg Val Trp Ala Glu Tyr Asp Pro Ala Ala 1715 1720 1725 tgt ggg cgc atc agt tac aat gac atg ttt gag atg ctg aaa cac 5349 Cys Gly Arg Ile Ser Tyr Asn Asp Met Phe Glu Met Leu Lys His 1730 1735 1740 atg tcc cca cct ctg ggg ttg ggg aag aaa tgc ccg gct cga gtt 5394 Met Ser Pro Pro Leu Gly Leu Gly Lys Lys Cys Pro Ala Arg Val 1745 1750 1755 gca tac aag cgc ctg gtt cgc atg aac atg ccc ata tcc aat gag 5439 Ala Tyr Lys Arg Leu Val Arg Met Asn Met Pro Ile Ser Asn Glu 1760 1765 1770 gac atg acg gtg cac ttt acg tcc aca ctg atg gcc ctc atc cgg 5484 Asp Met Thr Val His Phe Thr Ser Thr Leu Met Ala Leu Ile Arg 1775 1780 1785 aca gca ctg gag atc aag ctt gcc cca gct gac gag atg aca gtg 5529 Thr Ala Leu Glu Ile Lys Leu Ala Pro Ala Asp Glu Met Thr Val 1790 1795 1800 ggg aag gtc tat gct gct ctc atg ata ttt gac ttc tac aaa cag 5574 Gly Lys Val Tyr Ala Ala Leu Met Ile Phe Asp Phe Tyr Lys Gln 1805 1810 1815 aac aaa acc acc aga gat cag act cac caa gct ccc gga ggc ctg 5619 Asn Lys Thr Thr Arg Asp Gln Thr His Gln Ala Pro Gly Gly Leu 1820 1825 1830 tcc cag atg ggt ccc gtt tcc ctg ttc cac cct ctg aag gcc acc 5664 Ser Gln Met Gly Pro Val Ser Leu Phe His Pro Leu Lys Ala Thr 1835 1840 1845 ctg gaa cag aca cag ccc gct gtg ctt cga gga gct cgg gtt ttc 5709 Leu Glu Gln Thr Gln Pro Ala Val Leu Arg Gly Ala Arg Val Phe 1850 1855 1860 ctt cgg caa aag agt gca act tcc ctc agc aat ggg ggt gcc ata 5754 Leu Arg Gln Lys Ser Ala Thr Ser Leu Ser Asn Gly Gly Ala Ile 1865 1870 1875 caa acc cag gaa agt gga tca agg agt cgc tgt cct ggg gga cgc 5799 Gln Thr Gln Glu Ser Gly Ser Arg Ser Arg Cys Pro Gly Gly Arg 1880 1885 1890 aga ggg acc caa gat gca ctt tat gag ggc aga gca cct cta gaa 5844 Arg Gly Thr Gln Asp Ala Leu Tyr Glu Gly Arg Ala Pro Leu Glu 1895 1900 1905 cgt gac cat tct aaa gag atc cct gtg ggg cag tca gga aca ctg 5889 Arg Asp His Ser Lys Glu Ile Pro Val Gly Gln Ser Gly Thr Leu 1910 1915 1920 ctg gtg gat gtc cag atg cag aac atg aca ctg aga gga cca gat 5934 Leu Val Asp Val Gln Met Gln Asn Met Thr Leu Arg Gly Pro Asp 1925 1930 1935 ggg gat ccc cag cct ggc ctg gaa agc caa ggc aga gct gcc tct 5979 Gly Asp Pro Gln Pro Gly Leu Glu Ser Gln Gly Arg Ala Ala Ser 1940 1945 1950 atg cta cgc cta gcg gca gaa aca cag ccg gcc cct aat gcc agc 6024 Met Leu Arg Leu Ala Ala Glu Thr Gln Pro Ala Pro Asn Ala Ser 1955 1960 1965 ccc atg aag cgc tcc atc tcc aca ctg gct cca cgc cca gat ggg 6069 Pro Met Lys Arg Ser Ile Ser Thr Leu Ala Pro Arg Pro Asp Gly 1970 1975 1980 act cag ctt tgc agc aca gtt ctg gac cgg cct cct cct agc cag 6114 Thr Gln Leu Cys Ser Thr Val Leu Asp Arg Pro Pro Pro Ser Gln 1985 1990 1995 gca tca cat cac cac cac cac cgc tgc cac cgg cgc aga gac aag 6159 Ala Ser His His His His His Arg Cys His Arg Arg Arg Asp Lys 2000 2005 2010 aag caa agg tcc ctg gaa aag ggg ccc agc ctg tct gtt gac cca 6204 Lys Gln Arg Ser Leu Glu Lys Gly Pro Ser Leu Ser Val Asp Pro 2015 2020 2025 gaa ggt gca cca agc act gct gct gca gga cct ggt ctg ccc cat 6249 Glu Gly Ala Pro Ser Thr Ala Ala Ala Gly Pro Gly Leu Pro His 2030 2035 2040 gga gaa gga tcc acc gcc tgc cgg cgg gac cgt aaa cag gag cga 6294 Gly Glu Gly Ser Thr Ala Cys Arg Arg Asp Arg Lys Gln Glu Arg 2045 2050 2055 ggc cgg tcc cag gag cgg agg cag ccc tca tct tcc tct tca gag 6339 Gly Arg Ser Gln Glu Arg Arg Gln Pro Ser Ser Ser Ser Ser Glu 2060 2065 2070 aag cag cgc ttc tat tcc tgt gac cgc ttg gga gcc ggg agc ccc 6384 Lys Gln Arg Phe Tyr Ser Cys Asp Arg Leu Gly Ala Gly Ser Pro 2075 2080 2085 caa ctg atg ccc tca ctc agt agc cac ccc aca tcg ccg gcg gcg 6429 Gln Leu Met Pro Ser Leu Ser Ser His Pro Thr Ser Pro Ala Ala 2090 2095 2100 gcg cta gag cca gca ccc cac cca cag ggc agt ggt tcc gtt aat 6474 Ala Leu Glu Pro Ala Pro His Pro Gln Gly Ser Gly Ser Val Asn 2105 2110 2115 ggg agc ccc ttg atg tca aca tcc ggt gct att act ccc ggg cga 6519 Gly Ser Pro Leu Met Ser Thr Ser Gly Ala Ile Thr Pro Gly Arg 2120 2125 2130 ggt ggg cgg agg cag ctc ccc cag act cct ctg acc cca cgc ccc 6564 Gly Gly Arg Arg Gln Leu Pro Gln Thr Pro Leu Thr Pro Arg Pro 2135 2140 2145 agc atc acc tac aag acc gcc aat tcc tcg cct gtc cac ttt gct 6609 Ser Ile Thr Tyr Lys Thr Ala Asn Ser Ser Pro Val His Phe Ala 2150 2155 2160 gag ggt cag agc ggc ctc cca gcc ttc tcc cct ggc cgt ctc agc 6654 Glu Gly Gln Ser Gly Leu Pro Ala Phe Ser Pro Gly Arg Leu Ser 2165 2170 2175 cgc ggc ctt tct gaa cac aat gcc ctg ctc cag aaa gag ccc ctg 6699 Arg Gly Leu Ser Glu His Asn Ala Leu Leu Gln Lys Glu Pro Leu 2180 2185 2190 agc cag cct cta gct cct ggc tcc cga att ggc tct gac cct tac 6744 Ser Gln Pro Leu Ala Pro Gly Ser Arg Ile Gly Ser Asp Pro Tyr 2195 2200 2205 cta ggg cag cgt ctg gac agt gag gcc tcc gcc cac acc ctg cct 6789 Leu Gly Gln Arg Leu Asp Ser Glu Ala Ser Ala His Thr Leu Pro 2210 2215 2220 gag gat aca ctc acc ttt gaa gag gca gtg gcc acc aac tct ggc 6834 Glu Asp Thr Leu Thr Phe Glu Glu Ala Val Ala Thr Asn Ser Gly 2225 2230 2235 cgc tcc tcc agg act tcc tat gtg tcc tcc ctc act tcc caa tcc 6879 Arg Ser Ser Arg Thr Ser Tyr Val Ser Ser Leu Thr Ser Gln Ser 2240 2245 2250 cac cct ctc cgc cgt gta ccc aat ggc tat cac tgc act ttg gga 6924 His Pro Leu Arg Arg Val Pro Asn Gly Tyr His Cys Thr Leu Gly 2255 2260 2265 ctc aac act ggc gtc ggg gca cga gca agc tac cac cac ccc gat 6969 Leu Asn Thr Gly Val Gly Ala Arg Ala Ser Tyr His His Pro Asp 2270 2275 2280 cag gac cac tgg tgc tag cttcaccacg accacccatg taccagctcc 7017 Gln Asp His Trp Cys 2285 atgggtgagg gttccagttg atgagtttta tcatcccact ctggactgtg gggtcacaac 7077 cctgggagga gggccctcac atctcggcct ctgtggtgga ggctcctgct tccctccctc 7137 cctccctttt tacactggat agactaataa agccctttct tagagggg 7185 40 2288 PRT Mus musculus 40 Met Val Arg Phe Gly Asp Glu Leu Gly Gly Arg Tyr Gly Gly Thr Gly 1 5 10 15 Gly Gly Glu Arg Ala Arg Gly Gly Gly Ala Gly Gly Ala Gly Gly Pro 20 25 30 Gly Gln Gly Gly Leu Pro Pro Gly Gln Arg Val Leu Tyr Lys Gln Ser 35 40 45 Ile Ala Gln Arg Ala Arg Thr Met Ala Leu Tyr Asn Pro Ile Pro Val 50 55 60 Lys Gln Asn Cys Phe Thr Val Asn Arg Ser Leu Phe Val Phe Ser Glu 65 70 75 80 Asp Asn Val Val Arg Lys Tyr Ala Lys Arg Ile Thr Glu Trp Pro Pro 85 90 95 Phe Glu Tyr Met Ile Leu Ala Thr Ile Ile Ala Asn Cys Ile Val Leu 100 105 110 Ala Leu Glu Gln His Leu Pro Asp Gly Asp Lys Thr Pro Met Ser Glu 115 120 125 Arg Leu Asp Asp Thr Glu Pro Tyr Phe Ile Gly Ile Phe Cys Phe Glu 130 135 140 Ala Gly Ile Lys Ile Ile Ala Leu Gly Phe Val Phe His Lys Gly Ser 145 150 155 160 Tyr Leu Arg Asn Gly Trp Asn Val Met Asp Phe Val Val Val Leu Thr 165 170 175 Gly Ile Leu Ala Thr Ala Gly Thr Asp Phe Asp Leu Arg Thr Leu Arg 180 185 190 Ala Val Arg Val Leu Arg Pro Leu Lys Leu Val Ser Gly Ile Pro Ser 195 200 205 Leu Gln Val Val Leu Lys Ser Ile Met Lys Ala Met Val Pro Leu Leu 210 215 220 Gln Ile Gly Leu Leu Leu Phe Phe Ala Ile Leu Met Phe Gly Ile Ile 225 230 235 240 Gly Leu Glu Phe Tyr Met Gly Lys Phe His Lys Ala Cys Phe Pro Asn 245 250 255 Ser Thr Asp Thr Glu Pro Val Gly Asp Phe Pro Cys Gly Lys Asp Pro 260 265 270 Pro Ala Arg Gln Cys Asp Gly Asp Thr Glu Cys Arg Glu Tyr Trp Pro 275 280 285 Gly Pro Asn Phe Gly Ile Thr Asn Phe Asp Asn Ile Leu Phe Ala Ile 290 295 300 Leu Thr Val Phe Gln Cys Ile Thr Met Glu Gly Trp Thr Asp Ile Leu 305 310 315 320 Tyr Asn Thr Asn Asp Ala Ala Gly Asn Thr Trp Asn Trp Leu Tyr Phe 325 330 335 Ile Pro Leu Ile Ile Ile Gly Ser Phe Phe Met Leu Asn Leu Val Leu 340 345 350 Gly Val Leu Ser Gly Glu Phe Ala Lys Glu Arg Glu Arg Val Glu Asn 355 360 365 Arg Arg Ala Phe Leu Lys Leu Arg Arg Gln Gln Gln Ile Glu Arg Glu 370 375 380 Leu Asn Gly Tyr Leu Glu Trp Ile Phe Lys Ala Glu Glu Val Met Leu 385 390 395 400 Ala Glu Glu Asp Lys Asn Ala Glu Glu Lys Ser Pro Leu Asp Val Leu 405 410 415 Lys Arg Ala Ala Thr Lys Lys Ser Arg Asn Asp Leu Ile His Ala Glu 420 425 430 Glu Gly Glu Asp Arg Phe Val Asp Leu Cys Ala Val Gly Ser Pro Phe 435 440 445 Ala Arg Ala Ser Leu Lys Ser Gly Lys Thr Glu Ser Ser Ser Tyr Phe 450 455 460 Arg Arg Lys Glu Lys Met Phe Arg Phe Phe Ile Arg Arg Met Val Lys 465 470 475 480 Ala Gln Ser Phe Tyr Trp Val Val Leu Cys Val Val Ala Leu Asn Thr 485 490 495 Leu Cys Val Ala Met Val His Tyr Asn Gln Pro Gln Arg Leu Thr Thr 500 505 510 Ala Leu Tyr Phe Ala Glu Phe Val Phe Leu Gly Leu Phe Leu Thr Glu 515 520 525 Met Ser Leu Lys Met Tyr Gly Leu Gly Pro Arg Ser Tyr Phe Arg Ser 530 535 540 Ser Phe Asn Cys Phe Asp Phe Gly Val Ile Val Gly Ser Ile Phe Glu 545 550 555 560 Val Val Trp Ala Ala Ile Lys Pro Gly Thr Ser Phe Gly Ile Ser Val 565 570 575 Leu Arg Ala Leu Arg Leu Leu Arg Ile Phe Lys Val Thr Lys Tyr Trp 580 585 590 Asn Ser Leu Arg Asn Leu Val Val Ser Leu Leu Asn Ser Met Lys Ser 595 600 605 Ile Ile Ser Leu Leu Phe Leu Leu Phe Leu Phe Ile Val Val Phe Ala 610 615 620 Leu Leu Gly Met Gln Leu Phe Gly Gly Gln Phe Asn Phe Gln Asp Glu 625 630 635 640 Thr Pro Thr Thr Ile Phe Asp Thr Phe Pro Ala Ala Ile Leu Thr Val 645 650 655 Phe Gln Ile Leu Thr Gly Glu Asp Trp Asn Ala Val Met Tyr His Gly 660 665 670 Ile Glu Ser Gln Gly Gly Val Ser Lys Gly Met Phe Ser Ser Phe Tyr 675 680 685 Phe Ile Val Leu Thr Leu Phe Gly Asn Tyr Thr Leu Leu Asn Val Phe 690 695 700 Leu Ala Ile Ala Val Asp Asn Leu Ala Asn Ala Gln Glu Leu Thr Lys 705 710 715 720 Asp Glu Glu Glu Met Glu Glu Ala Ala Asn Gln Lys Leu Ala Leu Gln 725 730 735 Lys Ala Lys Glu Val Ala Glu Val Ser Pro Met Ser Ala Ala Asn Ile 740 745 750 Ser Ile Ala Ala Gln Glu Asn Ser Ala Lys Ala Arg Ser Val Trp Glu 755 760 765 Gln Arg Ala Ser Gln Leu Arg Leu Gln Asn Leu Arg Ala Ser Cys Glu 770 775 780 Ala Leu Tyr Ser Glu Met Asp Pro Glu Glu Arg Leu Arg Tyr Ala Ser 785 790 795 800 Thr Arg His Val Arg Pro Asp Met Lys Thr His Met Asp Arg Pro Leu 805 810 815 Val Val Glu Pro Gly Arg Asp Gly Leu Arg Gly Pro Val Gly Ser Lys 820 825 830 Ser Lys Pro Glu Gly Thr Glu Ala Thr Glu Ser Ala Asp Leu Pro Arg 835 840 845 Arg His His Arg His Arg Asp Arg Asp Lys Thr Ser Ala Thr Ala Pro 850 855 860 Ala Gly Gly Glu Gln Asp Arg Thr Glu Ser Thr Glu Thr Gly Pro Arg 865 870 875 880 Glu Glu Arg Ala Arg Pro Arg Arg Ser His Ser Lys Glu Thr Pro Gly 885 890 895 Ala Asp Thr Gln Val Arg Cys Glu Arg Ser Arg Arg His His Arg Arg 900 905 910 Gly Ser Pro Glu Glu Ala Thr Glu Arg Glu Pro Arg Arg His Arg Ala 915 920 925 His Arg His Ala Gln Asp Ser Ser Lys Glu Gly Thr Ala Pro Val Leu 930 935 940 Val Pro Lys Gly Glu Arg Arg Ala Arg His Arg Gly Pro Arg Thr Gly 945 950 955 960 Pro Arg Glu Ala Glu Asn Asn Glu Glu Pro Thr Arg Arg His Arg Ala 965 970 975 Arg His Lys Val Pro Pro Thr Leu Gln Pro Pro Glu Arg Glu Ala Ala 980 985 990 Glu Lys Glu Ser Asn Ala Val Glu Gly Asp Lys Glu Thr Arg Asn His 995 1000 1005 Gln Pro Lys Glu Pro His Cys Asp Leu Glu Ala Ile Ala Val Thr 1010 1015 1020 Gly Val Gly Pro Leu His Met Leu Pro Ser Thr Cys Leu Gln Lys 1025 1030 1035 Val Asp Glu Gln Pro Glu Asp Ala Asp Asn Gln Arg Asn Val Thr 1040 1045 1050 Arg Met Gly Ser Gln Pro Ser Asp Pro Ser Thr Thr Val His Val 1055 1060 1065 Pro Val Thr Leu Thr Gly Pro Pro Gly Glu Thr Pro Val Val Pro 1070 1075 1080 Ser Gly Asn Met Asn Leu Glu Gly Gln Ala Glu Gly Lys Lys Glu 1085 1090 1095 Ala Glu Ala Asp Asp Val Leu Arg Arg Gly Pro Arg Pro Ile Val 1100 1105 1110 Pro Tyr Ser Ser Met Phe Cys Leu Ser Pro Thr Asn Leu Phe Arg 1115 1120 1125 Arg Phe Cys His Tyr Ile Val Thr Met Arg Tyr Leu Glu Met Val 1130 1135 1140 Ile Leu Val Val Ile Ala Leu Ser Ser Ile Ala Leu Ala Ala Glu 1145 1150 1155 Asp Pro Val Arg Thr Asp Ser Phe Arg Asn Asn Ala Leu Glu Tyr 1160 1165 1170 Met Asp Tyr Ile Phe Thr Gly Val Phe Thr Cys Glu Met Val Ile 1175 1180 1185 Lys Met Ile Asp Leu Gly Leu Leu Leu His Pro Gly Ala Tyr Phe 1190 1195 1200 Arg Asp Leu Trp Asn Ile Leu Asp Phe Ile Val Val Ser Gly Ala 1205 1210 1215 Leu Val Ala Phe Ala Phe Ser Gly Ser Lys Gly Lys Asp Ile Asn 1220 1225 1230 Thr Ile Lys Ser Leu Arg Val Leu Arg Val Leu Arg Pro Leu Lys 1235 1240 1245 Thr Ile Lys Arg Leu Pro Lys Leu Lys Ala Val Phe Asp Cys Val 1250 1255 1260 Val Asn Ser Leu Lys Asn Val Leu Asn Ile Leu Ile Val Tyr Met 1265 1270 1275 Leu Phe Met Phe Ile Phe Ala Val Ile Ala Val Gln Leu Phe Lys 1280 1285 1290 Gly Lys Phe Phe Tyr Cys Thr Asp Glu Ser Lys Glu Leu Glu Arg 1295 1300 1305 Asp Cys Arg Gly Gln Tyr Leu Asp Tyr Glu Lys Glu Glu Val Glu 1310 1315 1320 Ala Gln Pro Arg Gln Trp Lys Lys Tyr Asp Phe His Tyr Asp Asn 1325 1330 1335 Val Leu Trp Ala Leu Leu Thr Leu Phe Thr Val Ser Thr Gly Glu 1340 1345 1350 Gly Trp Pro Met Val Leu Lys His Ser Val Asp Ala Thr Tyr Glu 1355 1360 1365 Glu Gln Gly Pro Ser Pro Gly Phe Arg Met Glu Leu Ser Ile Leu 1370 1375 1380 Tyr Val Val Tyr Phe Val Val Phe Pro Phe Phe Phe Val Asn Ile 1385 1390 1395 Phe Val Ala Leu Ile Ile Ile Thr Phe Gln Glu Gln Gly Asp Lys 1400 1405 1410 Val Met Ser Glu Cys Ser Leu Glu Lys Asn Glu Arg Ala Cys Ile 1415 1420 1425 Asp Phe Ala Ile Ser Ala Lys Pro Leu Thr Arg Tyr Met Pro Gln 1430 1435 1440 Asn Lys Gln Ser Phe Gln Tyr Lys Thr Trp Thr Phe Val Val Ser 1445 1450 1455 Pro Pro Phe Glu Tyr Phe Ile Met Ala Met Ile Ala Leu Asn Thr 1460 1465 1470 Val Val Leu Met Met Lys Phe Tyr Asp Ala Pro Tyr Glu Tyr Glu 1475 1480 1485 Leu Met Leu Lys Cys Leu Asn Ile Val Phe Thr Ser Met Phe Ser 1490 1495 1500 Met Glu Cys Ile Leu Lys Ile Ile Ala Phe Gly Val Leu Asn Tyr 1505 1510 1515 Phe Arg Asp Ala Trp Asn Val Phe Asp Phe Val Thr Val Leu Gly 1520 1525 1530 Ser Ile Thr Asp Ile Leu Val Thr Glu Ile Ala Glu Thr Asn Asn 1535 1540 1545 Phe Ile Asn Leu Ser Phe Leu Arg Leu Phe Arg Ala Ala Arg Leu 1550 1555 1560 Ile Lys Leu Leu Arg Gln Gly Tyr Thr Ile Arg Ile Leu Leu Trp 1565 1570 1575 Thr Phe Val Gln Ser Phe Lys Ala Leu Pro Tyr Val Cys Leu Leu 1580 1585 1590 Ile Ala Met Leu Phe Phe Ile Tyr Ala Ile Ile Gly Met Gln Val 1595 1600 1605 Phe Gly Asn Ser Ala Leu Asp Asp Asp Thr Ser Ile Asn Arg His 1610 1615 1620 Asn Asn Phe Arg Thr Phe Leu Gln Ala Ile Met Leu Leu Phe Arg 1625 1630 1635 Ser Ala Thr Gly Glu Ala Trp His Glu Ile Met Leu Ser Cys Leu 1640 1645 1650 Asp Asn Arg Ala Cys Asp Pro His Ala Asn Ala Ser Glu Cys Gly 1655 1660 1665 Ser Asp Phe Ala Tyr Phe Tyr Phe Val Ser Phe Ile Phe Leu Cys 1670 1675 1680 Ser Phe Leu Met Leu Asn Leu Phe Val Ala Val Ile Met Asp Asn 1685 1690 1695 Phe Glu Tyr Leu Thr Arg Asp Ser Ser Ile Leu Gly Pro His His 1700 1705 1710 Leu Asp Glu Phe Ile Arg Val Trp Ala Glu Tyr Asp Pro Ala Ala 1715 1720 1725 Cys Gly Arg Ile Ser Tyr Asn Asp Met Phe Glu Met Leu Lys His 1730 1735 1740 Met Ser Pro Pro Leu Gly Leu Gly Lys Lys Cys Pro Ala Arg Val 1745 1750 1755 Ala Tyr Lys Arg Leu Val Arg Met Asn Met Pro Ile Ser Asn Glu 1760 1765 1770 Asp Met Thr Val His Phe Thr Ser Thr Leu Met Ala Leu Ile Arg 1775 1780 1785 Thr Ala Leu Glu Ile Lys Leu Ala Pro Ala Asp Glu Met Thr Val 1790 1795 1800 Gly Lys Val Tyr Ala Ala Leu Met Ile Phe Asp Phe Tyr Lys Gln 1805 1810 1815 Asn Lys Thr Thr Arg Asp Gln Thr His Gln Ala Pro Gly Gly Leu 1820 1825 1830 Ser Gln Met Gly Pro Val Ser Leu Phe His Pro Leu Lys Ala Thr 1835 1840 1845 Leu Glu Gln Thr Gln Pro Ala Val Leu Arg Gly Ala Arg Val Phe 1850 1855 1860 Leu Arg Gln Lys Ser Ala Thr Ser Leu Ser Asn Gly Gly Ala Ile 1865 1870 1875 Gln Thr Gln Glu Ser Gly Ser Arg Ser Arg Cys Pro Gly Gly Arg 1880 1885 1890 Arg Gly Thr Gln Asp Ala Leu Tyr Glu Gly Arg Ala Pro Leu Glu 1895 1900 1905 Arg Asp His Ser Lys Glu Ile Pro Val Gly Gln Ser Gly Thr Leu 1910 1915 1920 Leu Val Asp Val Gln Met Gln Asn Met Thr Leu Arg Gly Pro Asp 1925 1930 1935 Gly Asp Pro Gln Pro Gly Leu Glu Ser Gln Gly Arg Ala Ala Ser 1940 1945 1950 Met Leu Arg Leu Ala Ala Glu Thr Gln Pro Ala Pro Asn Ala Ser 1955 1960 1965 Pro Met Lys Arg Ser Ile Ser Thr Leu Ala Pro Arg Pro Asp Gly 1970 1975 1980 Thr Gln Leu Cys Ser Thr Val Leu Asp Arg Pro Pro Pro Ser Gln 1985 1990 1995 Ala Ser His His His His His Arg Cys His Arg Arg Arg Asp Lys 2000 2005 2010 Lys Gln Arg Ser Leu Glu Lys Gly Pro Ser Leu Ser Val Asp Pro 2015 2020 2025 Glu Gly Ala Pro Ser Thr Ala Ala Ala Gly Pro Gly Leu Pro His 2030 2035 2040 Gly Glu Gly Ser Thr Ala Cys Arg Arg Asp Arg Lys Gln Glu Arg 2045 2050 2055 Gly Arg Ser Gln Glu Arg Arg Gln Pro Ser Ser Ser Ser Ser Glu 2060 2065 2070 Lys Gln Arg Phe Tyr Ser Cys Asp Arg Leu Gly Ala Gly Ser Pro 2075 2080 2085 Gln Leu Met Pro Ser Leu Ser Ser His Pro Thr Ser Pro Ala Ala 2090 2095 2100 Ala Leu Glu Pro Ala Pro His Pro Gln Gly Ser Gly Ser Val Asn 2105 2110 2115 Gly Ser Pro Leu Met Ser Thr Ser Gly Ala Ile Thr Pro Gly Arg 2120 2125 2130 Gly Gly Arg Arg Gln Leu Pro Gln Thr Pro Leu Thr Pro Arg Pro 2135 2140 2145 Ser Ile Thr Tyr Lys Thr Ala Asn Ser Ser Pro Val His Phe Ala 2150 2155 2160 Glu Gly Gln Ser Gly Leu Pro Ala Phe Ser Pro Gly Arg Leu Ser 2165 2170 2175 Arg Gly Leu Ser Glu His Asn Ala Leu Leu Gln Lys Glu Pro Leu 2180 2185 2190 Ser Gln Pro Leu Ala Pro Gly Ser Arg Ile Gly Ser Asp Pro Tyr 2195 2200 2205 Leu Gly Gln Arg Leu Asp Ser Glu Ala Ser Ala His Thr Leu Pro 2210 2215 2220 Glu Asp Thr Leu Thr Phe Glu Glu Ala Val Ala Thr Asn Ser Gly 2225 2230 2235 Arg Ser Ser Arg Thr Ser Tyr Val Ser Ser Leu Thr Ser Gln Ser 2240 2245 2250 His Pro Leu Arg Arg Val Pro Asn Gly Tyr His Cys Thr Leu Gly 2255 2260 2265 Leu Asn Thr Gly Val Gly Ala Arg Ala Ser Tyr His His Pro Asp 2270 2275 2280 Gln Asp His Trp Cys 2285 41 7713 DNA Oryctolagus cuniculus CDS (121)..(7140) 41 ggccgggccg ggcggggtcc ggtgcggtcc ggcagctccg cggcggcttc gtctcgatcg 60 cctggcgcgc cctccctgcc ggagccgccg ggccggggat gcgcgcggcg cccggtggcc 120 atg gtc cgc ttc ggg gac gag ctg ggc ggc cgc tat ggg ggc gcg ggc 168 Met Val Arg Phe Gly Asp Glu Leu Gly Gly Arg Tyr Gly Gly Ala Gly 1 5 10 15 ggc gcg gag cgg gcc cgg ggc ggc ggg gcc ggc ggg gct ggc ggc ccg 216 Gly Ala Glu Arg Ala Arg Gly Gly Gly Ala Gly Gly Ala Gly Gly Pro 20 25 30 ggc ccc ggg ggg ctg ccg ccg ggc cag cgg gtc ctc tac aaa cag tcg 264 Gly Pro Gly Gly Leu Pro Pro Gly Gln Arg Val Leu Tyr Lys Gln Ser 35 40 45 atc gcg cag cgc gcg cgg acc atg gcg ctg tac aac ccc atc ccg gtc 312 Ile Ala Gln Arg Ala Arg Thr Met Ala Leu Tyr Asn Pro Ile Pro Val 50 55 60 aag cag aac tgc ttc acc gtc aac cgc tcg ctc ttc gtc ttc agc gag 360 Lys Gln Asn Cys Phe Thr Val Asn Arg Ser Leu Phe Val Phe Ser Glu 65 70 75 80 gac aac gtc gtc cgc aaa tac gcc aag cgc atc acc gag tgg cct ccg 408 Asp Asn Val Val Arg Lys Tyr Ala Lys Arg Ile Thr Glu Trp Pro Pro 85 90 95 ttc gag tac atg atc ctg gcc acc atc atc gcc aac tgc atc gtg ctg 456 Phe Glu Tyr Met Ile Leu Ala Thr Ile Ile Ala Asn Cys Ile Val Leu 100 105 110 gcc ctg gag cag cac ctc cct gac ggg gac aag acg cct atg tcc gag 504 Ala Leu Glu Gln His Leu Pro Asp Gly Asp Lys Thr Pro Met Ser Glu 115 120 125 cgc ctg gat gac acc gag ccc tac ttc att ggg atc ttc tgc ttc gag 552 Arg Leu Asp Asp Thr Glu Pro Tyr Phe Ile Gly Ile Phe Cys Phe Glu 130 135 140 gcg ggg atc aag atc ctg gcc ctg ggc ttt gtt ctg cac aag ggc tcc 600 Ala Gly Ile Lys Ile Leu Ala Leu Gly Phe Val Leu His Lys Gly Ser 145 150 155 160 tat ctg cgg aac ggc tgg aac gtc atg gac ttc gtg gta gtc ctc acg 648 Tyr Leu Arg Asn Gly Trp Asn Val Met Asp Phe Val Val Val Leu Thr 165 170 175 ggg att ctt gcc aca gcc gga acc gac ttc gac ctg cga acg ctg agg 696 Gly Ile Leu Ala Thr Ala Gly Thr Asp Phe Asp Leu Arg Thr Leu Arg 180 185 190 gct gtg cgt gtg cta agg ccc ctg aag ctg gtg tct ggg att ccg agc 744 Ala Val Arg Val Leu Arg Pro Leu Lys Leu Val Ser Gly Ile Pro Ser 195 200 205 ttg cag gtg gtg ctc aag tcc atc atg aag gcc atg gtc ccg ctg ctg 792 Leu Gln Val Val Leu Lys Ser Ile Met Lys Ala Met Val Pro Leu Leu 210 215 220 cag atc ggg ctg ctg ctc ttc ttc gcc atc ctc atg ttt gcc atc atc 840 Gln Ile Gly Leu Leu Leu Phe Phe Ala Ile Leu Met Phe Ala Ile Ile 225 230 235 240 ggc ctc gag ttc tac atg ggc aag ttc cac aag gcc tgc ttc ccc aac 888 Gly Leu Glu Phe Tyr Met Gly Lys Phe His Lys Ala Cys Phe Pro Asn 245 250 255 agc aca gac cca gat ccc gtg ggt gac ttc ccc tgt ggc aag gag gcc 936 Ser Thr Asp Pro Asp Pro Val Gly Asp Phe Pro Cys Gly Lys Glu Ala 260 265 270 ccg gcc cgg ctc tgt gag gga gac acg gag tgc cgg gag tac tgg gcc 984 Pro Ala Arg Leu Cys Glu Gly Asp Thr Glu Cys Arg Glu Tyr Trp Ala 275 280 285 gga ccc aac ttt ggt atc acc aac ttt gac aac atc ctg ttt gcc atc 1032 Gly Pro Asn Phe Gly Ile Thr Asn Phe Asp Asn Ile Leu Phe Ala Ile 290 295 300 ttg acc gtg ttc cag tgc atc acc atg gag ggc tgg act gac atc ctc 1080 Leu Thr Val Phe Gln Cys Ile Thr Met Glu Gly Trp Thr Asp Ile Leu 305 310 315 320 tac aat aca aac gat gca gcc ggc aac acg tgg aac tgg ctc tac ttc 1128 Tyr Asn Thr Asn Asp Ala Ala Gly Asn Thr Trp Asn Trp Leu Tyr Phe 325 330 335 atc cct ctc atc atc atc ggc tcc ttc ttc atg ctc aac ctg gtg ctg 1176 Ile Pro Leu Ile Ile Ile Gly Ser Phe Phe Met Leu Asn Leu Val Leu 340 345 350 ggt gtg ctc tca gga gag ttt gct aag gag cgc gag aga gtg gag aac 1224 Gly Val Leu Ser Gly Glu Phe Ala Lys Glu Arg Glu Arg Val Glu Asn 355 360 365 cgc cgc gcc ttc ctg aag ctc cgg cgg cag cag cag att gag cgg gag 1272 Arg Arg Ala Phe Leu Lys Leu Arg Arg Gln Gln Gln Ile Glu Arg Glu 370 375 380 ctc aac ggg tac ctg gag tgg atc ttc aag gct gag gaa gtc atg ctg 1320 Leu Asn Gly Tyr Leu Glu Trp Ile Phe Lys Ala Glu Glu Val Met Leu 385 390 395 400 gct gag gag gac agg aac gca gag gag aag tcc cct ctg gat gca gtg 1368 Ala Glu Glu Asp Arg Asn Ala Glu Glu Lys Ser Pro Leu Asp Ala Val 405 410 415 ttg aag aga gca gct gcc aag aag agc aga agc gac ctg atc cag gcc 1416 Leu Lys Arg Ala Ala Ala Lys Lys Ser Arg Ser Asp Leu Ile Gln Ala 420 425 430 gag gag ggg gag ggc cgg ctc aca ggc ctc tgt gct ccc ggt tcc ccg 1464 Glu Glu Gly Glu Gly Arg Leu Thr Gly Leu Cys Ala Pro Gly Ser Pro 435 440 445 ttc gcc cgt gcc agc ctg aaa agc ggg aag acg gag agc tcg tcg tac 1512 Phe Ala Arg Ala Ser Leu Lys Ser Gly Lys Thr Glu Ser Ser Ser Tyr 450 455 460 ttc cgg agg aag gag aag atg ttc cgc ttc ttc atc cgg cgc atg gtg 1560 Phe Arg Arg Lys Glu Lys Met Phe Arg Phe Phe Ile Arg Arg Met Val 465 470 475 480 aag gca cag agc ttc tac tgg acg gtg ctg tgt gtg gtg gca ctg aac 1608 Lys Ala Gln Ser Phe Tyr Trp Thr Val Leu Cys Val Val Ala Leu Asn 485 490 495 aca ctg tgc gtg gcc atg gtg cac tac aac cag ccg cag cgg ctc acc 1656 Thr Leu Cys Val Ala Met Val His Tyr Asn Gln Pro Gln Arg Leu Thr 500 505 510 acg gca ttg tac ttt gca gag ttt gtt ttc ctg ggt ctc ttc ctc aca 1704 Thr Ala Leu Tyr Phe Ala Glu Phe Val Phe Leu Gly Leu Phe Leu Thr 515 520 525 gag atg tcc ctg aag atg tat ggc ctg ggg ccc agg agc tac ttc cgg 1752 Glu Met Ser Leu Lys Met Tyr Gly Leu Gly Pro Arg Ser Tyr Phe Arg 530 535 540 tcc tcc ttc aac tgt ttt gac ttt ggg gtc atc gtg ggc agt atc ttt 1800 Ser Ser Phe Asn Cys Phe Asp Phe Gly Val Ile Val Gly Ser Ile Phe 545 550 555 560 gaa gtg gtc tgg gct gct gtc aag cca ggg acc tcc ttc ggg atc agt 1848 Glu Val Val Trp Ala Ala Val Lys Pro Gly Thr Ser Phe Gly Ile Ser 565 570 575 gtt ctg cgg gct ctg cgc tta ctg aga atc ttc aag gtc acc aaa tac 1896 Val Leu Arg Ala Leu Arg Leu Leu Arg Ile Phe Lys Val Thr Lys Tyr 580 585 590 tgg aac tcc cta cgg aac ctg gtg gtg tct ctg ctc aac tcc atg aag 1944 Trp Asn Ser Leu Arg Asn Leu Val Val Ser Leu Leu Asn Ser Met Lys 595 600 605 tcc atc atc agc ctc ctc ttc ctg ctc ttc ctg ttc att gtt gtc ttt 1992 Ser Ile Ile Ser Leu Leu Phe Leu Leu Phe Leu Phe Ile Val Val Phe 610 615 620 gct ctg ctg ggg atg cag ctg ttt gga ggc cag ttc aac ttt aaa gac 2040 Ala Leu Leu Gly Met Gln Leu Phe Gly Gly Gln Phe Asn Phe Lys Asp 625 630 635 640 gag acc cca acg acc aac ttt gac acc ttc cct gct gct atc ctc acc 2088 Glu Thr Pro Thr Thr Asn Phe Asp Thr Phe Pro Ala Ala Ile Leu Thr 645 650 655 gtc ttc cag atc ctg acc gga gag gac tgg aat gcg gtc atg tac cac 2136 Val Phe Gln Ile Leu Thr Gly Glu Asp Trp Asn Ala Val Met Tyr His 660 665 670 ggg atc gag tcg caa ggt ggc gtc agc aga gga atg ttc tcc tcc ttc 2184 Gly Ile Glu Ser Gln Gly Gly Val Ser Arg Gly Met Phe Ser Ser Phe 675 680 685 tac ttc att gtc ctc act ctg ttt ggg aac tac acc ctg ctg aat gtc 2232 Tyr Phe Ile Val Leu Thr Leu Phe Gly Asn Tyr Thr Leu Leu Asn Val 690 695 700 ttc ctg gcc att gct gtg gac aac ctt gcc aat gct cag gag ctg acc 2280 Phe Leu Ala Ile Ala Val Asp Asn Leu Ala Asn Ala Gln Glu Leu Thr 705 710 715 720 aag gat gaa gag gag atg gaa gaa gca gcc aat cag aaa ctc gcc ttg 2328 Lys Asp Glu Glu Glu Met Glu Glu Ala Ala Asn Gln Lys Leu Ala Leu 725 730 735 cag aag gcc aag gaa gtg gct gaa gtc agc ccc atg tct gct gcg aac 2376 Gln Lys Ala Lys Glu Val Ala Glu Val Ser Pro Met Ser Ala Ala Asn 740 745 750 atc tcc att gcc gcc agg cag cag aac tcg gcc aaa gcg cgc tcg gtg 2424 Ile Ser Ile Ala Ala Arg Gln Gln Asn Ser Ala Lys Ala Arg Ser Val 755 760 765 tgg gag cag cga gcc agc cag ctg cgg ctg cag aac ctg agg gcc agc 2472 Trp Glu Gln Arg Ala Ser Gln Leu Arg Leu Gln Asn Leu Arg Ala Ser 770 775 780 tgc gag gcg ctg tac agc gag atg gac ccc gag gag agg ctg cgc tac 2520 Cys Glu Ala Leu Tyr Ser Glu Met Asp Pro Glu Glu Arg Leu Arg Tyr 785 790 795 800 gcc acc gcg cgc cac ctg cgg ccc gac gtg aag acg cac ctg gac cgg 2568 Ala Thr Ala Arg His Leu Arg Pro Asp Val Lys Thr His Leu Asp Arg 805 810 815 ccg ctg gtg gtt gag ccc ggc cgc gac gct ccg cgg ggc ccc ccg ggg 2616 Pro Leu Val Val Glu Pro Gly Arg Asp Ala Pro Arg Gly Pro Pro Gly 820 825 830 ggg aag tcc cgg ccg gat ggc tcg gag gcc ccc gag ggt gcg gat ccc 2664 Gly Lys Ser Arg Pro Asp Gly Ser Glu Ala Pro Glu Gly Ala Asp Pro 835 840 845 ccg cgc agg cat cac cgg cac cga gac aag gac aag gct ccc gcc acg 2712 Pro Arg Arg His His Arg His Arg Asp Lys Asp Lys Ala Pro Ala Thr 850 855 860 gtc ccc tcg gcg ggg gaa cag gac aga gcc gaa gct ctg agg gca gag 2760 Val Pro Ser Ala Gly Glu Gln Asp Arg Ala Glu Ala Leu Arg Ala Glu 865 870 875 880 ggc ggg gag ctg ggg ccc cgc gag gag cgg ggg cgg cca cgc cgc agc 2808 Gly Gly Glu Leu Gly Pro Arg Glu Glu Arg Gly Arg Pro Arg Arg Ser 885 890 895 cgc agc aag gag gcc ccg ggc gcc ccg gag gtg cgc agc gat cgc ggc 2856 Arg Ser Lys Glu Ala Pro Gly Ala Pro Glu Val Arg Ser Asp Arg Gly 900 905 910 cgt ggc ccg tgt cct gaa ggt ggt cgg cgc cac cac cgg cgc ggg tca 2904 Arg Gly Pro Cys Pro Glu Gly Gly Arg Arg His His Arg Arg Gly Ser 915 920 925 ccg gag gag gca gct gag agg gag ccc cgc cgc cac cgc gcg cac cgg 2952 Pro Glu Glu Ala Ala Glu Arg Glu Pro Arg Arg His Arg Ala His Arg 930 935 940 cac ggg ccc gac ccg ggc aag gag ggc cca gcg tcc ggg acc agg ggc 3000 His Gly Pro Asp Pro Gly Lys Glu Gly Pro Ala Ser Gly Thr Arg Gly 945 950 955 960 gag cgg cgc gca cga cac cgc acg ggc ccc cgg gcg tgc ccc cgg gag 3048 Glu Arg Arg Ala Arg His Arg Thr Gly Pro Arg Ala Cys Pro Arg Glu 965 970 975 gct gag agc agc gag gag cct gcg cgg cgg cac cgg gct cgg cac aag 3096 Ala Glu Ser Ser Glu Glu Pro Ala Arg Arg His Arg Ala Arg His Lys 980 985 990 gcg ccg ccc acc cag gag acc gcg gag aag gac aag gag gct gcc gag 3144 Ala Pro Pro Thr Gln Glu Thr Ala Glu Lys Asp Lys Glu Ala Ala Glu 995 1000 1005 aag ggg ggc gag gcc acg gag gcc gag aag gac aag gag gct cgg 3189 Lys Gly Gly Glu Ala Thr Glu Ala Glu Lys Asp Lys Glu Ala Arg 1010 1015 1020 aac cac cag ccc aag gag ctg ccc tgt gac ctg gag gcc atc ggc 3234 Asn His Gln Pro Lys Glu Leu Pro Cys Asp Leu Glu Ala Ile Gly 1025 1030 1035 atg ctg gga gtg ggc gct gtg cat acg ctg ccc agc acc tgt ctg 3279 Met Leu Gly Val Gly Ala Val His Thr Leu Pro Ser Thr Cys Leu 1040 1045 1050 cag aag gtg gag gag cag cca gag gat gcg gac aac cag cgg aac 3324 Gln Lys Val Glu Glu Gln Pro Glu Asp Ala Asp Asn Gln Arg Asn 1055 1060 1065 gtc acc cgc atg ggt agt cag ccc ccg gac acc agc acc act gtg 3369 Val Thr Arg Met Gly Ser Gln Pro Pro Asp Thr Ser Thr Thr Val 1070 1075 1080 cac att cct gtg acg ctg acc ggc ccc ccc ggg gag acc acg gta 3414 His Ile Pro Val Thr Leu Thr Gly Pro Pro Gly Glu Thr Thr Val 1085 1090 1095 gtg ccc agt gga aac gtg gac ctg gaa agt caa gca gag ggg aag 3459 Val Pro Ser Gly Asn Val Asp Leu Glu Ser Gln Ala Glu Gly Lys 1100 1105 1110 aag gag gtg gaa acc agc gat gtg atg agg agc ggc cct cgg ccc 3504 Lys Glu Val Glu Thr Ser Asp Val Met Arg Ser Gly Pro Arg Pro 1115 1120 1125 att gtc ccg tac agt tcc atg ttc tgt tta agc cca acc aac ctg 3549 Ile Val Pro Tyr Ser Ser Met Phe Cys Leu Ser Pro Thr Asn Leu 1130 1135 1140 ctg cgc cgc tgc tgc cac tac att gtg acc atg cga tac ttc gag 3594 Leu Arg Arg Cys Cys His Tyr Ile Val Thr Met Arg Tyr Phe Glu 1145 1150 1155 atg gtc atc ctc gtg gtc atc gcc ctg agc agc atc gcc ctg gct 3639 Met Val Ile Leu Val Val Ile Ala Leu Ser Ser Ile Ala Leu Ala 1160 1165 1170 gcc gag gac ccc gtg aga aca gac tct ccc agg aat aat gct ctg 3684 Ala Glu Asp Pro Val Arg Thr Asp Ser Pro Arg Asn Asn Ala Leu 1175 1180 1185 aag tac atg gac tac atc ttc aca ggc gtc ttc acc ttc gag atg 3729 Lys Tyr Met Asp Tyr Ile Phe Thr Gly Val Phe Thr Phe Glu Met 1190 1195 1200 gtg ata aag atg atc gat ttg gga ctg ctg cta cac cct gga gcc 3774 Val Ile Lys Met Ile Asp Leu Gly Leu Leu Leu His Pro Gly Ala 1205 1210 1215 tat ttc cgg gat ctg tgg aac att ctg gac ttc att gtg gtc agt 3819 Tyr Phe Arg Asp Leu Trp Asn Ile Leu Asp Phe Ile Val Val Ser 1220 1225 1230 ggg gcc ctg gtg gca ttt gct ttc tca gga tcc aaa ggg aaa gac 3864 Gly Ala Leu Val Ala Phe Ala Phe Ser Gly Ser Lys Gly Lys Asp 1235 1240 1245 atc agc acc atc aaa tcc ctg aga gtc ctg cgt gtg ctg cgg cca 3909 Ile Ser Thr Ile Lys Ser Leu Arg Val Leu Arg Val Leu Arg Pro 1250 1255 1260 ctc aag acc atc aag cgg ctg ccc aag ctc aag gcc gtg ttt gac 3954 Leu Lys Thr Ile Lys Arg Leu Pro Lys Leu Lys Ala Val Phe Asp 1265 1270 1275 tgt gtg gtg aac tca ctg aaa aac gtc ctc aac atc ctg atc gtc 3999 Cys Val Val Asn Ser Leu Lys Asn Val Leu Asn Ile Leu Ile Val 1280 1285 1290 tac atg ctc ttc atg ttc atc ttt gcc gtc att gcc gtg cag ctc 4044 Tyr Met Leu Phe Met Phe Ile Phe Ala Val Ile Ala Val Gln Leu 1295 1300 1305 ttc aaa ggg aag ttc ttc tac tgc acg gac gaa tcc aag gag ctg 4089 Phe Lys Gly Lys Phe Phe Tyr Cys Thr Asp Glu Ser Lys Glu Leu 1310 1315 1320 gag cgt gac tgc agg ggt cag tat ttg gat tat gag aag gag gaa 4134 Glu Arg Asp Cys Arg Gly Gln Tyr Leu Asp Tyr Glu Lys Glu Glu 1325 1330 1335 gtg gaa gct caa ccg agg cag tgg aag aaa tat gac ttc cac tat 4179 Val Glu Ala Gln Pro Arg Gln Trp Lys Lys Tyr Asp Phe His Tyr 1340 1345 1350 gac aac gtg ctc tgg gct ctg cta acg ctc ttc acg gtg tcc aca 4224 Asp Asn Val Leu Trp Ala Leu Leu Thr Leu Phe Thr Val Ser Thr 1355 1360 1365 ggg gaa ggg tgg ccc atg gtg ctg aaa cac tct gtg gat gcc acc 4269 Gly Glu Gly Trp Pro Met Val Leu Lys His Ser Val Asp Ala Thr 1370 1375 1380 tac gag gag cag ggc ccg agc ccc ggg tac cgc atg gag ctc tcc 4314 Tyr Glu Glu Gln Gly Pro Ser Pro Gly Tyr Arg Met Glu Leu Ser 1385 1390 1395 atc ttc tac gtg gtc tac ttt gtg gtc ttt ccc ttc ttc ttt gtc 4359 Ile Phe Tyr Val Val Tyr Phe Val Val Phe Pro Phe Phe Phe Val 1400 1405 1410 aac atc ttc gtg gcc ttg atc atc atc acc ttc cag gag cag ggg 4404 Asn Ile Phe Val Ala Leu Ile Ile Ile Thr Phe Gln Glu Gln Gly 1415 1420 1425 gac aag gtg atg tcc gag tgc agc ctg gag aag aac gag agg gct 4449 Asp Lys Val Met Ser Glu Cys Ser Leu Glu Lys Asn Glu Arg Ala 1430 1435 1440 tgc atc gac ttt gcc atc agc gcc aga ccc ctg acg cgg tac atg 4494 Cys Ile Asp Phe Ala Ile Ser Ala Arg Pro Leu Thr Arg Tyr Met 1445 1450 1455 ccc cag aac aag cag tcg ttc cag tat aag acg tgg acg ttc gtg 4539 Pro Gln Asn Lys Gln Ser Phe Gln Tyr Lys Thr Trp Thr Phe Val 1460 1465 1470 gtg tcc cca cct ttt gag tac ttc atc atg gct atg atc gcc ctc 4584 Val Ser Pro Pro Phe Glu Tyr Phe Ile Met Ala Met Ile Ala Leu 1475 1480 1485 aac act gtg gtg ctg atg atg aag ttc tac gat gcg ccg tac gag 4629 Asn Thr Val Val Leu Met Met Lys Phe Tyr Asp Ala Pro Tyr Glu 1490 1495 1500 tat gag cta atg ctg aaa tgc ctg aac atc gtg ttc acg tcc atg 4674 Tyr Glu Leu Met Leu Lys Cys Leu Asn Ile Val Phe Thr Ser Met 1505 1510 1515 ttc tcc atg gag tgt gtg ctg aag atc atc gcc ttc ggg gtg ctg 4719 Phe Ser Met Glu Cys Val Leu Lys Ile Ile Ala Phe Gly Val Leu 1520 1525 1530 aac tat ttc aga gat gcc tgg aat gtc ttt gac ttt gtc acg gtg 4764 Asn Tyr Phe Arg Asp Ala Trp Asn Val Phe Asp Phe Val Thr Val 1535 1540 1545 ttg gga agt att act gat att ttg gta aca gag att gcg aac aac 4809 Leu Gly Ser Ile Thr Asp Ile Leu Val Thr Glu Ile Ala Asn Asn 1550 1555 1560 ttc atc aac ctc agc ttc ctg cgc ctg ttc cgg gcc gcg cgg ctc 4854 Phe Ile Asn Leu Ser Phe Leu Arg Leu Phe Arg Ala Ala Arg Leu 1565 1570 1575 atc aag ctg ctg cgc cag ggc tac acc atc cgc atc ctg ctt tgg 4899 Ile Lys Leu Leu Arg Gln Gly Tyr Thr Ile Arg Ile Leu Leu Trp 1580 1585 1590 acc ttc gtg cag tcc ttc aag gcg ctg ccc tac gtg tgt ctc ctc 4944 Thr Phe Val Gln Ser Phe Lys Ala Leu Pro Tyr Val Cys Leu Leu 1595 1600 1605 atc gcc atg ctc ttc ttc atc tac gcc atc att ggc atg cag gtt 4989 Ile Ala Met Leu Phe Phe Ile Tyr Ala Ile Ile Gly Met Gln Val 1610 1615 1620 ttt ggg aac atc gcc ctg gac gat gac acc agc atc aac agg cac 5034 Phe Gly Asn Ile Ala Leu Asp Asp Asp Thr Ser Ile Asn Arg His 1625 1630 1635 aat aac ttc cgg acg ttt ctg cag gcc ttg atg ttg ctg ttc agg 5079 Asn Asn Phe Arg Thr Phe Leu Gln Ala Leu Met Leu Leu Phe Arg 1640 1645 1650 agc gcc acg ggg gag gcc tgg cac gag ata atg ctg tcg tgc ctc 5124 Ser Ala Thr Gly Glu Ala Trp His Glu Ile Met Leu Ser Cys Leu 1655 1660 1665 agc agc cgg gcc tgc gac gag cac tcc aat gcc agc gag tgc ggc 5169 Ser Ser Arg Ala Cys Asp Glu His Ser Asn Ala Ser Glu Cys Gly 1670 1675 1680 agc gac ttt gcc tac ttt tac ttc gtc tcc ttc atc ttc ctc tgc 5214 Ser Asp Phe Ala Tyr Phe Tyr Phe Val Ser Phe Ile Phe Leu Cys 1685 1690 1695 tcc ttt ctg atg ttg aac ctc ttt gtg gct gtg atc atg gac aat 5259 Ser Phe Leu Met Leu Asn Leu Phe Val Ala Val Ile Met Asp Asn 1700 1705 1710 ttt gag tac ctt aca cgg gac tct tcc atc tta ggg cct cac cac 5304 Phe Glu Tyr Leu Thr Arg Asp Ser Ser Ile Leu Gly Pro His His 1715 1720 1725 ctg gat gag ttc atc cgg gtc tgg gct gaa tac gac ccg gcc gcg 5349 Leu Asp Glu Phe Ile Arg Val Trp Ala Glu Tyr Asp Pro Ala Ala 1730 1735 1740 tgt ggg cgc atc agt tac agt gac atg ttt gag atg ctg aag cac 5394 Cys Gly Arg Ile Ser Tyr Ser Asp Met Phe Glu Met Leu Lys His 1745 1750 1755 atg tcc cca ccc ctg ggg ctg ggg aag aag tgc cct gct cga gtc 5439 Met Ser Pro Pro Leu Gly Leu Gly Lys Lys Cys Pro Ala Arg Val 1760 1765 1770 gcg tac aag cgc ctg gtc cgc atg aac atg ccc atc tcc agt gag 5484 Ala Tyr Lys Arg Leu Val Arg Met Asn Met Pro Ile Ser Ser Glu 1775 1780 1785 gac atg acg gtg cac ttc aca tcc acg ctg atg gct ctc att cgg 5529 Asp Met Thr Val His Phe Thr Ser Thr Leu Met Ala Leu Ile Arg 1790 1795 1800 aca gcg ctg gac atc aag ctg gca cca gct ggg acc aag cag cac 5574 Thr Ala Leu Asp Ile Lys Leu Ala Pro Ala Gly Thr Lys Gln His 1805 1810 1815 cag tgc gac gca gag ctg agg aag gag att tcc tgt gtg tgg gcc 5619 Gln Cys Asp Ala Glu Leu Arg Lys Glu Ile Ser Cys Val Trp Ala 1820 1825 1830 aat ctg ccc cag aag acc ctg gac tta ctg gta cca ccc cat aag 5664 Asn Leu Pro Gln Lys Thr Leu Asp Leu Leu Val Pro Pro His Lys 1835 1840 1845 cct gac gag atg acg gtg ggc aaa gtc tat gca gct ctg atg atc 5709 Pro Asp Glu Met Thr Val Gly Lys Val Tyr Ala Ala Leu Met Ile 1850 1855 1860 ttc gac ttc tac aaa cag aac aaa acc agc aga gac cag act cag 5754 Phe Asp Phe Tyr Lys Gln Asn Lys Thr Ser Arg Asp Gln Thr Gln 1865 1870 1875 caa gcc ccc gga ggc ctg tcc cag ctg ggc ccc gtg tcc ctg ttc 5799 Gln Ala Pro Gly Gly Leu Ser Gln Leu Gly Pro Val Ser Leu Phe 1880 1885 1890 cac ccg ctg aag gcc acg ctg gag cag act cag ccg gcg ctg cgt 5844 His Pro Leu Lys Ala Thr Leu Glu Gln Thr Gln Pro Ala Leu Arg 1895 1900 1905 gga gcc cgg gct ttc ctg cgg cag aag agt tct gcc tcc ctg agc 5889 Gly Ala Arg Ala Phe Leu Arg Gln Lys Ser Ser Ala Ser Leu Ser 1910 1915 1920 aac ggc ggg gcc gta caa acc cag gag agc ggc atc aag gaa tcg 5934 Asn Gly Gly Ala Val Gln Thr Gln Glu Ser Gly Ile Lys Glu Ser 1925 1930 1935 gtt tct tgg ggc act cag agg acc cag gat gtg ctt tgc gag gcc 5979 Val Ser Trp Gly Thr Gln Arg Thr Gln Asp Val Leu Cys Glu Ala 1940 1945 1950 agg gca ccc ctg gag cgg ggc cac tca gct gag atc cca gtc ggg 6024 Arg Ala Pro Leu Glu Arg Gly His Ser Ala Glu Ile Pro Val Gly 1955 1960 1965 cag cct ggg aca ctg gct gta gat gtc cag atg cag aac atg act 6069 Gln Pro Gly Thr Leu Ala Val Asp Val Gln Met Gln Asn Met Thr 1970 1975 1980 ctg agt ggc cct gac gcc gag ccg cag cca ggg ctg gag agc cag 6114 Leu Ser Gly Pro Asp Ala Glu Pro Gln Pro Gly Leu Glu Ser Gln 1985 1990 1995 ggc cga gcc gcc tcc atg ccc cgc ctg gcc gca gaa aca cag ccc 6159 Gly Arg Ala Ala Ser Met Pro Arg Leu Ala Ala Glu Thr Gln Pro 2000 2005 2010 gcg cct gac gcc agc ccc atg aag cgc tcc atc tcc acg ctg gcc 6204 Ala Pro Asp Ala Ser Pro Met Lys Arg Ser Ile Ser Thr Leu Ala 2015 2020 2025 ccg cgc ccc cac acg gcc cgg ctc ggc agc acc gcg ctg gac cgc 6249 Pro Arg Pro His Thr Ala Arg Leu Gly Ser Thr Ala Leu Asp Arg 2030 2035 2040 cca gcc ccc agc cag gcc ccg cac cat cac cac cac cgc tgc cac 6294 Pro Ala Pro Ser Gln Ala Pro His His His His His Arg Cys His 2045 2050 2055 cgc cgc agg gac agg aag cag cgg tcc ctg gag aag ggt ccc agc 6339 Arg Arg Arg Asp Arg Lys Gln Arg Ser Leu Glu Lys Gly Pro Ser 2060 2065 2070 ctg tct gct gac aca gat ggg gcc ccc gac agc acg gtg ggg cca 6384 Leu Ser Ala Asp Thr Asp Gly Ala Pro Asp Ser Thr Val Gly Pro 2075 2080 2085 gga ctg ccc acg ggg gag ggc ccc ccc ggc tgc agg cgg gag cgg 6429 Gly Leu Pro Thr Gly Glu Gly Pro Pro Gly Cys Arg Arg Glu Arg 2090 2095 2100 gag cgc agg cag gag cgg ggc cgg tcc cag gag cgg agg cag ccc 6474 Glu Arg Arg Gln Glu Arg Gly Arg Ser Gln Glu Arg Arg Gln Pro 2105 2110 2115 tcg tcc tcc tcc tcg gag aag cat cgc ttc tac tcc tgt gac cgc 6519 Ser Ser Ser Ser Ser Glu Lys His Arg Phe Tyr Ser Cys Asp Arg 2120 2125 2130 ttc ggg ggc cgc gaa ccc cca cag ccc aag ccc tcc ctc agt agt 6564 Phe Gly Gly Arg Glu Pro Pro Gln Pro Lys Pro Ser Leu Ser Ser 2135 2140 2145 cac ccc acg tcg ccg acg gcc ggg cag gag ccg gga ccc cac ccg 6609 His Pro Thr Ser Pro Thr Ala Gly Gln Glu Pro Gly Pro His Pro 2150 2155 2160 cag ggg agt ggt tcg gtt cac ggg agc ccc ctg ctg tcc aca tct 6654 Gln Gly Ser Gly Ser Val His Gly Ser Pro Leu Leu Ser Thr Ser 2165 2170 2175 ggt gct agc acc ccg ggc cgg ggg cgg agg cag ctc ccc cag acc 6699 Gly Ala Ser Thr Pro Gly Arg Gly Arg Arg Gln Leu Pro Gln Thr 2180 2185 2190 ccc ttg acc ccc cgc ccc agc gtc acc tac aag acg gcc aac tcc 6744 Pro Leu Thr Pro Arg Pro Ser Val Thr Tyr Lys Thr Ala Asn Ser 2195 2200 2205 tcg cct gtc cac ttc gcc ggg gca ccg agc ggc ctc ccc gcc ttc 6789 Ser Pro Val His Phe Ala Gly Ala Pro Ser Gly Leu Pro Ala Phe 2210 2215 2220 tcc ccc ggc cgg ctc agc cgg ggc ctc tca gaa cac aac gcc ctg 6834 Ser Pro Gly Arg Leu Ser Arg Gly Leu Ser Glu His Asn Ala Leu 2225 2230 2235 ctg cag agg gac ccg ctc agc cgg ccc ctg gcg ccc ggc tcg cgc 6879 Leu Gln Arg Asp Pro Leu Ser Arg Pro Leu Ala Pro Gly Ser Arg 2240 2245 2250 atc ggc tcc gac ccc tac ctg ggg cag cgg ctg gac agc gag gcg 6924 Ile Gly Ser Asp Pro Tyr Leu Gly Gln Arg Leu Asp Ser Glu Ala 2255 2260 2265 ccc gcc cgt gcc ctg ccc gag gac gcg ccc gcc ttt gag gag acc 6969 Pro Ala Arg Ala Leu Pro Glu Asp Ala Pro Ala Phe Glu Glu Thr 2270 2275 2280 gcg gcc agc aac tcg ggc cgc tcc tcc cgg acc tcg tac gtg tcc 7014 Ala Ala Ser Asn Ser Gly Arg Ser Ser Arg Thr Ser Tyr Val Ser 2285 2290 2295 tca ctg acc tcg cag ccc ccg ccg ctg cgc cgc gtg ccc aac ggc 7059 Ser Leu Thr Ser Gln Pro Pro Pro Leu Arg Arg Val Pro Asn Gly 2300 2305 2310 tac cac tgc act ctg ggg ctg ggc ggg ggc ggc cgg gcg cgg cgc 7104 Tyr His Cys Thr Leu Gly Leu Gly Gly Gly Gly Arg Ala Arg Arg 2315 2320 2325 ggc tgc cac cac ccc gac cgc gac cgc cgg tgc tag ccgctgcgcg 7150 Gly Cys His His Pro Asp Arg Asp Arg Arg Cys 2330 2335 cccgcccccg gcggtgggct tcatcttccg cgctgggctg cggggacgcg ggcaccgagg 7210 ccctggacgg ggcctgggcg gaggcccctg ctcccctccc cctcctccct gacagcagac 7270 ggatcaataa agccccttcc ggcgggacgc ggctgtctct gccccctgac gtgctgcctt 7330 cccaggtctc ccaccacagg ctgatcctgt gtcagagacc ccggtgtcag tgtgcagggg 7390 tggggggtgc ggggcctgtg tcggaccccc agggttaatg gggggagcgt cagtgtgtgg 7450 gagcacctgt gacccgtgtt ggtgggagga gttgcactgc ctggaggcat aggggagctt 7510 aggggtctcg agggagccgg gggaggagct gaggttgctc ctggtccctg gtcgcggggc 7570 ggcaggtgga cgctggacac actcagatct ctcagtccct ccccgacccc atcagcccca 7630 acagggacca aacctggagg acgtgccggc tgctggtcta aacagaacag gaagaaaatg 7690 aggaaaccgg aaaatcagag ccg 7713 42 2339 PRT Oryctolagus cuniculus 42 Met Val Arg Phe Gly Asp Glu Leu Gly Gly Arg Tyr Gly Gly Ala Gly 1 5 10 15 Gly Ala Glu Arg Ala Arg Gly Gly Gly Ala Gly Gly Ala Gly Gly Pro 20 25 30 Gly Pro Gly Gly Leu Pro Pro Gly Gln Arg Val Leu Tyr Lys Gln Ser 35 40 45 Ile Ala Gln Arg Ala Arg Thr Met Ala Leu Tyr Asn Pro Ile Pro Val 50 55 60 Lys Gln Asn Cys Phe Thr Val Asn Arg Ser Leu Phe Val Phe Ser Glu 65 70 75 80 Asp Asn Val Val Arg Lys Tyr Ala Lys Arg Ile Thr Glu Trp Pro Pro 85 90 95 Phe Glu Tyr Met Ile Leu Ala Thr Ile Ile Ala Asn Cys Ile Val Leu 100 105 110 Ala Leu Glu Gln His Leu Pro Asp Gly Asp Lys Thr Pro Met Ser Glu 115 120 125 Arg Leu Asp Asp Thr Glu Pro Tyr Phe Ile Gly Ile Phe Cys Phe Glu 130 135 140 Ala Gly Ile Lys Ile Leu Ala Leu Gly Phe Val Leu His Lys Gly Ser 145 150 155 160 Tyr Leu Arg Asn Gly Trp Asn Val Met Asp Phe Val Val Val Leu Thr 165 170 175 Gly Ile Leu Ala Thr Ala Gly Thr Asp Phe Asp Leu Arg Thr Leu Arg 180 185 190 Ala Val Arg Val Leu Arg Pro Leu Lys Leu Val Ser Gly Ile Pro Ser 195 200 205 Leu Gln Val Val Leu Lys Ser Ile Met Lys Ala Met Val Pro Leu Leu 210 215 220 Gln Ile Gly Leu Leu Leu Phe Phe Ala Ile Leu Met Phe Ala Ile Ile 225 230 235 240 Gly Leu Glu Phe Tyr Met Gly Lys Phe His Lys Ala Cys Phe Pro Asn 245 250 255 Ser Thr Asp Pro Asp Pro Val Gly Asp Phe Pro Cys Gly Lys Glu Ala 260 265 270 Pro Ala Arg Leu Cys Glu Gly Asp Thr Glu Cys Arg Glu Tyr Trp Ala 275 280 285 Gly Pro Asn Phe Gly Ile Thr Asn Phe Asp Asn Ile Leu Phe Ala Ile 290 295 300 Leu Thr Val Phe Gln Cys Ile Thr Met Glu Gly Trp Thr Asp Ile Leu 305 310 315 320 Tyr Asn Thr Asn Asp Ala Ala Gly Asn Thr Trp Asn Trp Leu Tyr Phe 325 330 335 Ile Pro Leu Ile Ile Ile Gly Ser Phe Phe Met Leu Asn Leu Val Leu 340 345 350 Gly Val Leu Ser Gly Glu Phe Ala Lys Glu Arg Glu Arg Val Glu Asn 355 360 365 Arg Arg Ala Phe Leu Lys Leu Arg Arg Gln Gln Gln Ile Glu Arg Glu 370 375 380 Leu Asn Gly Tyr Leu Glu Trp Ile Phe Lys Ala Glu Glu Val Met Leu 385 390 395 400 Ala Glu Glu Asp Arg Asn Ala Glu Glu Lys Ser Pro Leu Asp Ala Val 405 410 415 Leu Lys Arg Ala Ala Ala Lys Lys Ser Arg Ser Asp Leu Ile Gln Ala 420 425 430 Glu Glu Gly Glu Gly Arg Leu Thr Gly Leu Cys Ala Pro Gly Ser Pro 435 440 445 Phe Ala Arg Ala Ser Leu Lys Ser Gly Lys Thr Glu Ser Ser Ser Tyr 450 455 460 Phe Arg Arg Lys Glu Lys Met Phe Arg Phe Phe Ile Arg Arg Met Val 465 470 475 480 Lys Ala Gln Ser Phe Tyr Trp Thr Val Leu Cys Val Val Ala Leu Asn 485 490 495 Thr Leu Cys Val Ala Met Val His Tyr Asn Gln Pro Gln Arg Leu Thr 500 505 510 Thr Ala Leu Tyr Phe Ala Glu Phe Val Phe Leu Gly Leu Phe Leu Thr 515 520 525 Glu Met Ser Leu Lys Met Tyr Gly Leu Gly Pro Arg Ser Tyr Phe Arg 530 535 540 Ser Ser Phe Asn Cys Phe Asp Phe Gly Val Ile Val Gly Ser Ile Phe 545 550 555 560 Glu Val Val Trp Ala Ala Val Lys Pro Gly Thr Ser Phe Gly Ile Ser 565 570 575 Val Leu Arg Ala Leu Arg Leu Leu Arg Ile Phe Lys Val Thr Lys Tyr 580 585 590 Trp Asn Ser Leu Arg Asn Leu Val Val Ser Leu Leu Asn Ser Met Lys 595 600 605 Ser Ile Ile Ser Leu Leu Phe Leu Leu Phe Leu Phe Ile Val Val Phe 610 615 620 Ala Leu Leu Gly Met Gln Leu Phe Gly Gly Gln Phe Asn Phe Lys Asp 625 630 635 640 Glu Thr Pro Thr Thr Asn Phe Asp Thr Phe Pro Ala Ala Ile Leu Thr 645 650 655 Val Phe Gln Ile Leu Thr Gly Glu Asp Trp Asn Ala Val Met Tyr His 660 665 670 Gly Ile Glu Ser Gln Gly Gly Val Ser Arg Gly Met Phe Ser Ser Phe 675 680 685 Tyr Phe Ile Val Leu Thr Leu Phe Gly Asn Tyr Thr Leu Leu Asn Val 690 695 700 Phe Leu Ala Ile Ala Val Asp Asn Leu Ala Asn Ala Gln Glu Leu Thr 705 710 715 720 Lys Asp Glu Glu Glu Met Glu Glu Ala Ala Asn Gln Lys Leu Ala Leu 725 730 735 Gln Lys Ala Lys Glu Val Ala Glu Val Ser Pro Met Ser Ala Ala Asn 740 745 750 Ile Ser Ile Ala Ala Arg Gln Gln Asn Ser Ala Lys Ala Arg Ser Val 755 760 765 Trp Glu Gln Arg Ala Ser Gln Leu Arg Leu Gln Asn Leu Arg Ala Ser 770 775 780 Cys Glu Ala Leu Tyr Ser Glu Met Asp Pro Glu Glu Arg Leu Arg Tyr 785 790 795 800 Ala Thr Ala Arg His Leu Arg Pro Asp Val Lys Thr His Leu Asp Arg 805 810 815 Pro Leu Val Val Glu Pro Gly Arg Asp Ala Pro Arg Gly Pro Pro Gly 820 825 830 Gly Lys Ser Arg Pro Asp Gly Ser Glu Ala Pro Glu Gly Ala Asp Pro 835 840 845 Pro Arg Arg His His Arg His Arg Asp Lys Asp Lys Ala Pro Ala Thr 850 855 860 Val Pro Ser Ala Gly Glu Gln Asp Arg Ala Glu Ala Leu Arg Ala Glu 865 870 875 880 Gly Gly Glu Leu Gly Pro Arg Glu Glu Arg Gly Arg Pro Arg Arg Ser 885 890 895 Arg Ser Lys Glu Ala Pro Gly Ala Pro Glu Val Arg Ser Asp Arg Gly 900 905 910 Arg Gly Pro Cys Pro Glu Gly Gly Arg Arg His His Arg Arg Gly Ser 915 920 925 Pro Glu Glu Ala Ala Glu Arg Glu Pro Arg Arg His Arg Ala His Arg 930 935 940 His Gly Pro Asp Pro Gly Lys Glu Gly Pro Ala Ser Gly Thr Arg Gly 945 950 955 960 Glu Arg Arg Ala Arg His Arg Thr Gly Pro Arg Ala Cys Pro Arg Glu 965 970 975 Ala Glu Ser Ser Glu Glu Pro Ala Arg Arg His Arg Ala Arg His Lys 980 985 990 Ala Pro Pro Thr Gln Glu Thr Ala Glu Lys Asp Lys Glu Ala Ala Glu 995 1000 1005 Lys Gly Gly Glu Ala Thr Glu Ala Glu Lys Asp Lys Glu Ala Arg 1010 1015 1020 Asn His Gln Pro Lys Glu Leu Pro Cys Asp Leu Glu Ala Ile Gly 1025 1030 1035 Met Leu Gly Val Gly Ala Val His Thr Leu Pro Ser Thr Cys Leu 1040 1045 1050 Gln Lys Val Glu Glu Gln Pro Glu Asp Ala Asp Asn Gln Arg Asn 1055 1060 1065 Val Thr Arg Met Gly Ser Gln Pro Pro Asp Thr Ser Thr Thr Val 1070 1075 1080 His Ile Pro Val Thr Leu Thr Gly Pro Pro Gly Glu Thr Thr Val 1085 1090 1095 Val Pro Ser Gly Asn Val Asp Leu Glu Ser Gln Ala Glu Gly Lys 1100 1105 1110 Lys Glu Val Glu Thr Ser Asp Val Met Arg Ser Gly Pro Arg Pro 1115 1120 1125 Ile Val Pro Tyr Ser Ser Met Phe Cys Leu Ser Pro Thr Asn Leu 1130 1135 1140 Leu Arg Arg Cys Cys His Tyr Ile Val Thr Met Arg Tyr Phe Glu 1145 1150 1155 Met Val Ile Leu Val Val Ile Ala Leu Ser Ser Ile Ala Leu Ala 1160 1165 1170 Ala Glu Asp Pro Val Arg Thr Asp Ser Pro Arg Asn Asn Ala Leu 1175 1180 1185 Lys Tyr Met Asp Tyr Ile Phe Thr Gly Val Phe Thr Phe Glu Met 1190 1195 1200 Val Ile Lys Met Ile Asp Leu Gly Leu Leu Leu His Pro Gly Ala 1205 1210 1215 Tyr Phe Arg Asp Leu Trp Asn Ile Leu Asp Phe Ile Val Val Ser 1220 1225 1230 Gly Ala Leu Val Ala Phe Ala Phe Ser Gly Ser Lys Gly Lys Asp 1235 1240 1245 Ile Ser Thr Ile Lys Ser Leu Arg Val Leu Arg Val Leu Arg Pro 1250 1255 1260 Leu Lys Thr Ile Lys Arg Leu Pro Lys Leu Lys Ala Val Phe Asp 1265 1270 1275 Cys Val Val Asn Ser Leu Lys Asn Val Leu Asn Ile Leu Ile Val 1280 1285 1290 Tyr Met Leu Phe Met Phe Ile Phe Ala Val Ile Ala Val Gln Leu 1295 1300 1305 Phe Lys Gly Lys Phe Phe Tyr Cys Thr Asp Glu Ser Lys Glu Leu 1310 1315 1320 Glu Arg Asp Cys Arg Gly Gln Tyr Leu Asp Tyr Glu Lys Glu Glu 1325 1330 1335 Val Glu Ala Gln Pro Arg Gln Trp Lys Lys Tyr Asp Phe His Tyr 1340 1345 1350 Asp Asn Val Leu Trp Ala Leu Leu Thr Leu Phe Thr Val Ser Thr 1355 1360 1365 Gly Glu Gly Trp Pro Met Val Leu Lys His Ser Val Asp Ala Thr 1370 1375 1380 Tyr Glu Glu Gln Gly Pro Ser Pro Gly Tyr Arg Met Glu Leu Ser 1385 1390 1395 Ile Phe Tyr Val Val Tyr Phe Val Val Phe Pro Phe Phe Phe Val 1400 1405 1410 Asn Ile Phe Val Ala Leu Ile Ile Ile Thr Phe Gln Glu Gln Gly 1415 1420 1425 Asp Lys Val Met Ser Glu Cys Ser Leu Glu Lys Asn Glu Arg Ala 1430 1435 1440 Cys Ile Asp Phe Ala Ile Ser Ala Arg Pro Leu Thr Arg Tyr Met 1445 1450 1455 Pro Gln Asn Lys Gln Ser Phe Gln Tyr Lys Thr Trp Thr Phe Val 1460 1465 1470 Val Ser Pro Pro Phe Glu Tyr Phe Ile Met Ala Met Ile Ala Leu 1475 1480 1485 Asn Thr Val Val Leu Met Met Lys Phe Tyr Asp Ala Pro Tyr Glu 1490 1495 1500 Tyr Glu Leu Met Leu Lys Cys Leu Asn Ile Val Phe Thr Ser Met 1505 1510 1515 Phe Ser Met Glu Cys Val Leu Lys Ile Ile Ala Phe Gly Val Leu 1520 1525 1530 Asn Tyr Phe Arg Asp Ala Trp Asn Val Phe Asp Phe Val Thr Val 1535 1540 1545 Leu Gly Ser Ile Thr Asp Ile Leu Val Thr Glu Ile Ala Asn Asn 1550 1555 1560 Phe Ile Asn Leu Ser Phe Leu Arg Leu Phe Arg Ala Ala Arg Leu 1565 1570 1575 Ile Lys Leu Leu Arg Gln Gly Tyr Thr Ile Arg Ile Leu Leu Trp 1580 1585 1590 Thr Phe Val Gln Ser Phe Lys Ala Leu Pro Tyr Val Cys Leu Leu 1595 1600 1605 Ile Ala Met Leu Phe Phe Ile Tyr Ala Ile Ile Gly Met Gln Val 1610 1615 1620 Phe Gly Asn Ile Ala Leu Asp Asp Asp Thr Ser Ile Asn Arg His 1625 1630 1635 Asn Asn Phe Arg Thr Phe Leu Gln Ala Leu Met Leu Leu Phe Arg 1640 1645 1650 Ser Ala Thr Gly Glu Ala Trp His Glu Ile Met Leu Ser Cys Leu 1655 1660 1665 Ser Ser Arg Ala Cys Asp Glu His Ser Asn Ala Ser Glu Cys Gly 1670 1675 1680 Ser Asp Phe Ala Tyr Phe Tyr Phe Val Ser Phe Ile Phe Leu Cys 1685 1690 1695 Ser Phe Leu Met Leu Asn Leu Phe Val Ala Val Ile Met Asp Asn 1700 1705 1710 Phe Glu Tyr Leu Thr Arg Asp Ser Ser Ile Leu Gly Pro His His 1715 1720 1725 Leu Asp Glu Phe Ile Arg Val Trp Ala Glu Tyr Asp Pro Ala Ala 1730 1735 1740 Cys Gly Arg Ile Ser Tyr Ser Asp Met Phe Glu Met Leu Lys His 1745 1750 1755 Met Ser Pro Pro Leu Gly Leu Gly Lys Lys Cys Pro Ala Arg Val 1760 1765 1770 Ala Tyr Lys Arg Leu Val Arg Met Asn Met Pro Ile Ser Ser Glu 1775 1780 1785 Asp Met Thr Val His Phe Thr Ser Thr Leu Met Ala Leu Ile Arg 1790 1795 1800 Thr Ala Leu Asp Ile Lys Leu Ala Pro Ala Gly Thr Lys Gln His 1805 1810 1815 Gln Cys Asp Ala Glu Leu Arg Lys Glu Ile Ser Cys Val Trp Ala 1820 1825 1830 Asn Leu Pro Gln Lys Thr Leu Asp Leu Leu Val Pro Pro His Lys 1835 1840 1845 Pro Asp Glu Met Thr Val Gly Lys Val Tyr Ala Ala Leu Met Ile 1850 1855 1860 Phe Asp Phe Tyr Lys Gln Asn Lys Thr Ser Arg Asp Gln Thr Gln 1865 1870 1875 Gln Ala Pro Gly Gly Leu Ser Gln Leu Gly Pro Val Ser Leu Phe 1880 1885 1890 His Pro Leu Lys Ala Thr Leu Glu Gln Thr Gln Pro Ala Leu Arg 1895 1900 1905 Gly Ala Arg Ala Phe Leu Arg Gln Lys Ser Ser Ala Ser Leu Ser 1910 1915 1920 Asn Gly Gly Ala Val Gln Thr Gln Glu Ser Gly Ile Lys Glu Ser 1925 1930 1935 Val Ser Trp Gly Thr Gln Arg Thr Gln Asp Val Leu Cys Glu Ala 1940 1945 1950 Arg Ala Pro Leu Glu Arg Gly His Ser Ala Glu Ile Pro Val Gly 1955 1960 1965 Gln Pro Gly Thr Leu Ala Val Asp Val Gln Met Gln Asn Met Thr 1970 1975 1980 Leu Ser Gly Pro Asp Ala Glu Pro Gln Pro Gly Leu Glu Ser Gln 1985 1990 1995 Gly Arg Ala Ala Ser Met Pro Arg Leu Ala Ala Glu Thr Gln Pro 2000 2005 2010 Ala Pro Asp Ala Ser Pro Met Lys Arg Ser Ile Ser Thr Leu Ala 2015 2020 2025 Pro Arg Pro His Thr Ala Arg Leu Gly Ser Thr Ala Leu Asp Arg 2030 2035 2040 Pro Ala Pro Ser Gln Ala Pro His His His His His Arg Cys His 2045 2050 2055 Arg Arg Arg Asp Arg Lys Gln Arg Ser Leu Glu Lys Gly Pro Ser 2060 2065 2070 Leu Ser Ala Asp Thr Asp Gly Ala Pro Asp Ser Thr Val Gly Pro 2075 2080 2085 Gly Leu Pro Thr Gly Glu Gly Pro Pro Gly Cys Arg Arg Glu Arg 2090 2095 2100 Glu Arg Arg Gln Glu Arg Gly Arg Ser Gln Glu Arg Arg Gln Pro 2105 2110 2115 Ser Ser Ser Ser Ser Glu Lys His Arg Phe Tyr Ser Cys Asp Arg 2120 2125 2130 Phe Gly Gly Arg Glu Pro Pro Gln Pro Lys Pro Ser Leu Ser Ser 2135 2140 2145 His Pro Thr Ser Pro Thr Ala Gly Gln Glu Pro Gly Pro His Pro 2150 2155 2160 Gln Gly Ser Gly Ser Val His Gly Ser Pro Leu Leu Ser Thr Ser 2165 2170 2175 Gly Ala Ser Thr Pro Gly Arg Gly Arg Arg Gln Leu Pro Gln Thr 2180 2185 2190 Pro Leu Thr Pro Arg Pro Ser Val Thr Tyr Lys Thr Ala Asn Ser 2195 2200 2205 Ser Pro Val His Phe Ala Gly Ala Pro Ser Gly Leu Pro Ala Phe 2210 2215 2220 Ser Pro Gly Arg Leu Ser Arg Gly Leu Ser Glu His Asn Ala Leu 2225 2230 2235 Leu Gln Arg Asp Pro Leu Ser Arg Pro Leu Ala Pro Gly Ser Arg 2240 2245 2250 Ile Gly Ser Asp Pro Tyr Leu Gly Gln Arg Leu Asp Ser Glu Ala 2255 2260 2265 Pro Ala Arg Ala Leu Pro Glu Asp Ala Pro Ala Phe Glu Glu Thr 2270 2275 2280 Ala Ala Ser Asn Ser Gly Arg Ser Ser Arg Thr Ser Tyr Val Ser 2285 2290 2295 Ser Leu Thr Ser Gln Pro Pro Pro Leu Arg Arg Val Pro Asn Gly 2300 2305 2310 Tyr His Cys Thr Leu Gly Leu Gly Gly Gly Gly Arg Ala Arg Arg 2315 2320 2325 Gly Cys His His Pro Asp Arg Asp Arg Arg Cys 2330 2335 43 7121 DNA Bos taurus CDS (126)..(7121) 43 ctgggcgagg tctggtgcgg gtccggcggc tccgcggctg ctccgctaga gcgcagggcg 60 cacctcgcgc cttccgatcc ccgcggggcc gccgggccgg gggatgcgct cagcgcccgg 120 gagcc atg gtc cgc ttc ggg gac gag ctg ggc ggc cgc tat ggg ggc ccc 170 Met Val Arg Phe Gly Asp Glu Leu Gly Gly Arg Tyr Gly Gly Pro 1 5 10 15 ggc ggt ggg gag cgg gcg cgg ggc ggc ggg gcc ggc gtt gcg ggc ggc 218 Gly Gly Gly Glu Arg Ala Arg Gly Gly Gly Ala Gly Val Ala Gly Gly 20 25 30 ccg ggc ccc ggg ggg ctg cag ccg ggc cag cgg gtc ctc tac aag cag 266 Pro Gly Pro Gly Gly Leu Gln Pro Gly Gln Arg Val Leu Tyr Lys Gln 35 40 45 tcg atc gcg cag cgc gcg cgg acc atg gcg ctg tac aac ccc atc ccg 314 Ser Ile Ala Gln Arg Ala Arg Thr Met Ala Leu Tyr Asn Pro Ile Pro 50 55 60 gtc aag cag aac tgc ttc acc gtc aac cgc tcg ctc ttc gtc ttc agc 362 Val Lys Gln Asn Cys Phe Thr Val Asn Arg Ser Leu Phe Val Phe Ser 65 70 75 gag gac aac gtc gtc cgc aaa tac gcc aag cgc atc acc gag tgg cct 410 Glu Asp Asn Val Val Arg Lys Tyr Ala Lys Arg Ile Thr Glu Trp Pro 80 85 90 95 ccg ttt gag tac atg att ctg gcc acc atc atc gcc aac tgt atc gtg 458 Pro Phe Glu Tyr Met Ile Leu Ala Thr Ile Ile Ala Asn Cys Ile Val 100 105 110 ctg gct ctg gag cag cac ctc cca gac gga gac aag acg ccc atg tct 506 Leu Ala Leu Glu Gln His Leu Pro Asp Gly Asp Lys Thr Pro Met Ser 115 120 125 gag cgg ctg gac gac acg gag ccc tac ttc atc ggc atc ttc tgc ttc 554 Glu Arg Leu Asp Asp Thr Glu Pro Tyr Phe Ile Gly Ile Phe Cys Phe 130 135 140 gag gct ggg atc aag atc atc gcg ctg ggc ttt gtc ttg cac aag ggc 602 Glu Ala Gly Ile Lys Ile Ile Ala Leu Gly Phe Val Leu His Lys Gly 145 150 155 tcc tac ctg cgg aat ggc tgg aac gtc atg gac ttc gtg gtg gtc ctc 650 Ser Tyr Leu Arg Asn Gly Trp Asn Val Met Asp Phe Val Val Val Leu 160 165 170 175 acg ggg atc ctc gcc aca gct ggc act gac ttt gat ctg cga aca ctg 698 Thr Gly Ile Leu Ala Thr Ala Gly Thr Asp Phe Asp Leu Arg Thr Leu 180 185 190 cgg gct gtg cgt gta ctg agg ccc ctg aag ctg gtg tct ggg att cca 746 Arg Ala Val Arg Val Leu Arg Pro Leu Lys Leu Val Ser Gly Ile Pro 195 200 205 agt ttg cag gtg gtg ctc aag tcc atc atg aag gcc atg gtc ccg ctc 794 Ser Leu Gln Val Val Leu Lys Ser Ile Met Lys Ala Met Val Pro Leu 210 215 220 ctg cag att ggg ctg ctt ctc ttt ttc gcc atc ctc atg ttc gcc atc 842 Leu Gln Ile Gly Leu Leu Leu Phe Phe Ala Ile Leu Met Phe Ala Ile 225 230 235 att ggc ctc gag ttc tac atg ggc aaa ttc cac aag gct tgt ttc ccc 890 Ile Gly Leu Glu Phe Tyr Met Gly Lys Phe His Lys Ala Cys Phe Pro 240 245 250 255 aac agc aca gac gca gat ccg gtg ggt gac ttc ccg tgc ggc agg gag 938 Asn Ser Thr Asp Ala Asp Pro Val Gly Asp Phe Pro Cys Gly Arg Glu 260 265 270 gcc ccg gcg cgg ctg tgc gag ggc gac act gag tgc cgg gag tac tgg 986 Ala Pro Ala Arg Leu Cys Glu Gly Asp Thr Glu Cys Arg Glu Tyr Trp 275 280 285 gcg ggc ccc aac ttc ggc atc acc aac ttc gac aac atc ctg ttc gcc 1034 Ala Gly Pro Asn Phe Gly Ile Thr Asn Phe Asp Asn Ile Leu Phe Ala 290 295 300 atc ctg acg gtg ttc cag tgc atc acc atg gag ggc tgg acc gac atc 1082 Ile Leu Thr Val Phe Gln Cys Ile Thr Met Glu Gly Trp Thr Asp Ile 305 310 315 ctc tac aac acc aac gac gcg gct ggc aac acc tgg aac tgg ctc tac 1130 Leu Tyr Asn Thr Asn Asp Ala Ala Gly Asn Thr Trp Asn Trp Leu Tyr 320 325 330 335 ttc ctg ccc ctg att atc atc ggc tcg ttc ttc atg ctc aac ctg gtg 1178 Phe Leu Pro Leu Ile Ile Ile Gly Ser Phe Phe Met Leu Asn Leu Val 340 345 350 ctg ggc gtg ctc tca gga gag ttt gcc aag gag cgt gag cgg gtg gag 1226 Leu Gly Val Leu Ser Gly Glu Phe Ala Lys Glu Arg Glu Arg Val Glu 355 360 365 aac cgc cgg gcc ttt ctg aag ctc cgc cgg cag cag cag atc gag cgg 1274 Asn Arg Arg Ala Phe Leu Lys Leu Arg Arg Gln Gln Gln Ile Glu Arg 370 375 380 gag ctc aat ggg tac ctg gag tgg atc ttc aag gcc gag gag gtc atg 1322 Glu Leu Asn Gly Tyr Leu Glu Trp Ile Phe Lys Ala Glu Glu Val Met 385 390 395 ctg gcc gag gag gac aag aac gca gag gag aag tcc cct ctg gat gtg 1370 Leu Ala Glu Glu Asp Lys Asn Ala Glu Glu Lys Ser Pro Leu Asp Val 400 405 410 415 ttg aag aga gca gcc acc aag aag agc cga aac gac ctg atc cac gcg 1418 Leu Lys Arg Ala Ala Thr Lys Lys Ser Arg Asn Asp Leu Ile His Ala 420 425 430 gag gag gga gag gac cgc ttt gca gac ctc tgt gct gtg ggg tcc ccc 1466 Glu Glu Gly Glu Asp Arg Phe Ala Asp Leu Cys Ala Val Gly Ser Pro 435 440 445 ttc gcc cga gcc agc ctc aag agt ggg aag acg gag agc tcg tca tac 1514 Phe Ala Arg Ala Ser Leu Lys Ser Gly Lys Thr Glu Ser Ser Ser Tyr 450 455 460 ttc cgc agg aag gag aag atg ttc cgg ttc ttc atc cgg cgc ctg gtg 1562 Phe Arg Arg Lys Glu Lys Met Phe Arg Phe Phe Ile Arg Arg Leu Val 465 470 475 aag gcg cag agc ttc tac tgg gtg gtg ctg tgt gtg gtg gcc ctg aac 1610 Lys Ala Gln Ser Phe Tyr Trp Val Val Leu Cys Val Val Ala Leu Asn 480 485 490 495 acg ctg tgc gtg gcc atg gtg cac tac cag cag ccc cag cgg ctc acc 1658 Thr Leu Cys Val Ala Met Val His Tyr Gln Gln Pro Gln Arg Leu Thr 500 505 510 acg gcg ctg tac ttt gca gag ttt gtt ttc ctg ggt ctc ttc ctc aca 1706 Thr Ala Leu Tyr Phe Ala Glu Phe Val Phe Leu Gly Leu Phe Leu Thr 515 520 525 gag atg tcc ctg aag atg tat ggc ctg ggg ccc agg agc tac ttc cgg 1754 Glu Met Ser Leu Lys Met Tyr Gly Leu Gly Pro Arg Ser Tyr Phe Arg 530 535 540 tcc tcc ttc aac tgc ttc gat ttc ggg gtc att gtg ggg agc att ttc 1802 Ser Ser Phe Asn Cys Phe Asp Phe Gly Val Ile Val Gly Ser Ile Phe 545 550 555 gaa gtg gtc tgg gcg gcc atc aag cca gga acc tcc ttc ggc atc agt 1850 Glu Val Val Trp Ala Ala Ile Lys Pro Gly Thr Ser Phe Gly Ile Ser 560 565 570 575 gtg ctg cgg gcg ctg cgg ctg ctg aga atc ttc aaa gtc acc aag tac 1898 Val Leu Arg Ala Leu Arg Leu Leu Arg Ile Phe Lys Val Thr Lys Tyr 580 585 590 tgg agc tcc ctg cgg aac ctg gtg gtg tcc ctg ctc aac tcc atg aag 1946 Trp Ser Ser Leu Arg Asn Leu Val Val Ser Leu Leu Asn Ser Met Lys 595 600 605 tcc atc atc agc ctg ctc ttc ctg ctc ttc ctc ttc atc gtg gtc ttc 1994 Ser Ile Ile Ser Leu Leu Phe Leu Leu Phe Leu Phe Ile Val Val Phe 610 615 620 gct ctg ctg ggc atg cag ctc ttc ggg gga cag ttc aac ttc cag gat 2042 Ala Leu Leu Gly Met Gln Leu Phe Gly Gly Gln Phe Asn Phe Gln Asp 625 630 635 gag act ccg aca acc aac ttt gac acc ttc cct gcc gcc atc ctc act 2090 Glu Thr Pro Thr Thr Asn Phe Asp Thr Phe Pro Ala Ala Ile Leu Thr 640 645 650 655 gtc ttc cag atc ctg acc ggg gag gac tgg aat gcg gtg atg tac cat 2138 Val Phe Gln Ile Leu Thr Gly Glu Asp Trp Asn Ala Val Met Tyr His 660 665 670 ggg atc gaa tca caa ggt gga gtc agc aag ggc atg ttc tcg tct gtg 2186 Gly Ile Glu Ser Gln Gly Gly Val Ser Lys Gly Met Phe Ser Ser Val 675 680 685 tac ttc att gtc ctg acg ctg ttt ggg aac tac acc ctg ctg aac gtc 2234 Tyr Phe Ile Val Leu Thr Leu Phe Gly Asn Tyr Thr Leu Leu Asn Val 690 695 700 ttc ctg gcc atc gct gtg gac aac ctc gcc aat gct cag gag ctg acc 2282 Phe Leu Ala Ile Ala Val Asp Asn Leu Ala Asn Ala Gln Glu Leu Thr 705 710 715 aag gac gaa gag gag atg gaa gaa gca gcc aat cag aag ctt gct ctg 2330 Lys Asp Glu Glu Glu Met Glu Glu Ala Ala Asn Gln Lys Leu Ala Leu 720 725 730 735 caa aag gcc aaa gaa gtg gct gaa gtc agc ccc atg tct gcc gcg aac 2378 Gln Lys Ala Lys Glu Val Ala Glu Val Ser Pro Met Ser Ala Ala Asn 740 745 750 atc tcc att gct gcc agg cag cag aac tcg gcc aag gcg cgc tcg gtg 2426 Ile Ser Ile Ala Ala Arg Gln Gln Asn Ser Ala Lys Ala Arg Ser Val 755 760 765 tgg gag cag cgg gcc agc cag ctg cgg ctg cag aac ctg cgg gcc agc 2474 Trp Glu Gln Arg Ala Ser Gln Leu Arg Leu Gln Asn Leu Arg Ala Ser 770 775 780 tgt gaa gcg ctg tat agc gag atg gac ccc gag gag cgc ctg cgc ttc 2522 Cys Glu Ala Leu Tyr Ser Glu Met Asp Pro Glu Glu Arg Leu Arg Phe 785 790 795 gcc act tcc cgc cac ctg cgg ccc gac atg aag acg cac ctg gac cgg 2570 Ala Thr Ser Arg His Leu Arg Pro Asp Met Lys Thr His Leu Asp Arg 800 805 810 815 ccg ctt gtg gtg gag cca ggc cgg gat ggc gcg cgg ggg cct gcg ggg 2618 Pro Leu Val Val Glu Pro Gly Arg Asp Gly Ala Arg Gly Pro Ala Gly 820 825 830 ggc aag gcc cgg ccc gag ggc gga gag gcc ggc gag ggt gcc gac ccg 2666 Gly Lys Ala Arg Pro Glu Gly Gly Glu Ala Gly Glu Gly Ala Asp Pro 835 840 845 ccg cgc agg cac cac cgg cac cgc gac agg gac agg gac aag gcc gca 2714 Pro Arg Arg His His Arg His Arg Asp Arg Asp Arg Asp Lys Ala Ala 850 855 860 gcc ccg gcg ggg gag cca gac agg gcg gac gcc ccg aag gcg gag ggc 2762 Ala Pro Ala Gly Glu Pro Asp Arg Ala Asp Ala Pro Lys Ala Glu Gly 865 870 875 ggg gag ccg ggg gcc cgg gag gag cgg gcg cga ccg cgc cgc agc cgc 2810 Gly Glu Pro Gly Ala Arg Glu Glu Arg Ala Arg Pro Arg Arg Ser Arg 880 885 890 895 agc aag gag gcc gca ggc ccc cgc gag gcc agg agc gag cga ggc cgc 2858 Ser Lys Glu Ala Ala Gly Pro Arg Glu Ala Arg Ser Glu Arg Gly Arg 900 905 910 ggg ctg ggc ccg gac ggc ggc cgg cgc cac cac cgg cgc ggc tcc ccg 2906 Gly Leu Gly Pro Asp Gly Gly Arg Arg His His Arg Arg Gly Ser Pro 915 920 925 gag gag gcc gcg gag cgc gag ccc cgg cgc cac cgc gcg cac cgg cac 2954 Glu Glu Ala Ala Glu Arg Glu Pro Arg Arg His Arg Ala His Arg His 930 935 940 gcg ccg gag ccg agc agg gag ggc gcg ccc ggg agc aag ggc gag cgg 3002 Ala Pro Glu Pro Ser Arg Glu Gly Ala Pro Gly Ser Lys Gly Glu Arg 945 950 955 cga gcg cgg cac cgc ggc ggc tcc cgg gcc ggg ccc cgg gag gcc gag 3050 Arg Ala Arg His Arg Gly Gly Ser Arg Ala Gly Pro Arg Glu Ala Glu 960 965 970 975 agc ggc gag gag ccc tcc cgg cgg cac cga gcg cga cac aag gcg ccg 3098 Ser Gly Glu Glu Pro Ser Arg Arg His Arg Ala Arg His Lys Ala Pro 980 985 990 ccc gca cac gag gag gcg gag aag gag gcc gag gcg gag gac agg gac 3146 Pro Ala His Glu Glu Ala Glu Lys Glu Ala Glu Ala Glu Asp Arg Asp 995 1000 1005 aag gag ccc cga aac cac cag ccc agg gag tcg cac tgt gac ctg 3191 Lys Glu Pro Arg Asn His Gln Pro Arg Glu Ser His Cys Asp Leu 1010 1015 1020 gag gcc agt gtg gtc att ggt gtg ggc cct gtg cat gcc ctg ccc 3236 Glu Ala Ser Val Val Ile Gly Val Gly Pro Val His Ala Leu Pro 1025 1030 1035 agc act tgt cta gag aag gtg gaa gag cag cca gag gat gca gac 3281 Ser Thr Cys Leu Glu Lys Val Glu Glu Gln Pro Glu Asp Ala Asp 1040 1045 1050 aat cag cgg aat gtg act cgc atg ggc agt cag ccc tca gat ctg 3326 Asn Gln Arg Asn Val Thr Arg Met Gly Ser Gln Pro Ser Asp Leu 1055 1060 1065 agc acc gct gtg cgt atc cca gtg acg ctg acc ggg cct ccc ggg 3371 Ser Thr Ala Val Arg Ile Pro Val Thr Leu Thr Gly Pro Pro Gly 1070 1075 1080 gag acc acg gtt gtt ccc agt ggt aac gtg gac ctg gaa agc caa 3416 Glu Thr Thr Val Val Pro Ser Gly Asn Val Asp Leu Glu Ser Gln 1085 1090 1095 gca gaa gga aag aag gag gtg gaa gct gat gac gtg atg agg agt 3461 Ala Glu Gly Lys Lys Glu Val Glu Ala Asp Asp Val Met Arg Ser 1100 1105 1110 ggc ccc cga ccc att gtc ccg tac agc tcc atg ttc tgc ttg agc 3506 Gly Pro Arg Pro Ile Val Pro Tyr Ser Ser Met Phe Cys Leu Ser 1115 1120 1125 ccc acc aac ctg ctc cgc cgc ttc tgc cac tac att gtg acc atg 3551 Pro Thr Asn Leu Leu Arg Arg Phe Cys His Tyr Ile Val Thr Met 1130 1135 1140 cag tac ttc gag atg gtc att ctc gtg gtc att gcc ctg agt agc 3596 Gln Tyr Phe Glu Met Val Ile Leu Val Val Ile Ala Leu Ser Ser 1145 1150 1155 att gcc ctg gct gcg gag gat cct gtg cag aca gac tcg ccc agg 3641 Ile Ala Leu Ala Ala Glu Asp Pro Val Gln Thr Asp Ser Pro Arg 1160 1165 1170 aac aac gtg ctg aag tac atg gac tac atc ttc aca ggt gtc ttc 3686 Asn Asn Val Leu Lys Tyr Met Asp Tyr Ile Phe Thr Gly Val Phe 1175 1180 1185 acc ttt gag atg gtg ata aag atg atc gat ttg gga ctg ctg ctg 3731 Thr Phe Glu Met Val Ile Lys Met Ile Asp Leu Gly Leu Leu Leu 1190 1195 1200 cac ccc ggt gcc tac ttc cgg gat ctg tgg aac att ctg gac ttc 3776 His Pro Gly Ala Tyr Phe Arg Asp Leu Trp Asn Ile Leu Asp Phe 1205 1210 1215 att gtg gtc agt ggg gcc ctg gtg gcg ttt gcc ttc tca ggc tcc 3821 Ile Val Val Ser Gly Ala Leu Val Ala Phe Ala Phe Ser Gly Ser 1220 1225 1230 aaa ggg aaa gac atc agc acc atc aag tcc ctg agg gtc ctg cgt 3866 Lys Gly Lys Asp Ile Ser Thr Ile Lys Ser Leu Arg Val Leu Arg 1235 1240 1245 gtg ctg agg cca ctc aag acc atc aag cgg ctg ccc aag ctc aaa 3911 Val Leu Arg Pro Leu Lys Thr Ile Lys Arg Leu Pro Lys Leu Lys 1250 1255 1260 gct gtg ttt gac tgt gtg gtg aac tcc ctg aag aac gtc ctc aac 3956 Ala Val Phe Asp Cys Val Val Asn Ser Leu Lys Asn Val Leu Asn 1265 1270 1275 atc ctg atc gtc tac atg ctc ttc atg ttc ata ttt gct gtc atc 4001 Ile Leu Ile Val Tyr Met Leu Phe Met Phe Ile Phe Ala Val Ile 1280 1285 1290 gcg gta cag ctc ttc aag ggg aag ttt ttc tac tgc acc gac gag 4046 Ala Val Gln Leu Phe Lys Gly Lys Phe Phe Tyr Cys Thr Asp Glu 1295 1300 1305 tcc aag gag ctg gag cgg gac tgc agg ggc cag tat ttg gac tac 4091 Ser Lys Glu Leu Glu Arg Asp Cys Arg Gly Gln Tyr Leu Asp Tyr 1310 1315 1320 gag aag gag gag gtg gaa gct cag ccg cgg cag tgg aag aaa tac 4136 Glu Lys Glu Glu Val Glu Ala Gln Pro Arg Gln Trp Lys Lys Tyr 1325 1330 1335 gac ttc cac tat gac aac gtg ctg tgg gcc ctg cta acg ctg ttc 4181 Asp Phe His Tyr Asp Asn Val Leu Trp Ala Leu Leu Thr Leu Phe 1340 1345 1350 act gtg tcc acg ggc gaa ggg tgg ccc atg gtg ctg aaa cac tcg 4226 Thr Val Ser Thr Gly Glu Gly Trp Pro Met Val Leu Lys His Ser 1355 1360 1365 gtg gat gcc acc tac gag gag cag ggc ccc agc ccc ggg ttc cgc 4271 Val Asp Ala Thr Tyr Glu Glu Gln Gly Pro Ser Pro Gly Phe Arg 1370 1375 1380 atg gag ctg tcc atc ttc tat gtg gtc tac ttc gtg gtc ttc ccc 4316 Met Glu Leu Ser Ile Phe Tyr Val Val Tyr Phe Val Val Phe Pro 1385 1390 1395 ttc ttc ttt gtg aac atc ttt gtg gcc ttg atc atc atc acc ttc 4361 Phe Phe Phe Val Asn Ile Phe Val Ala Leu Ile Ile Ile Thr Phe 1400 1405 1410 cag gag cag ggg gac aaa gtc atg tct gag tgc agc ttg gag aag 4406 Gln Glu Gln Gly Asp Lys Val Met Ser Glu Cys Ser Leu Glu Lys 1415 1420 1425 aac gag agg gct tgt atc gac ttc gcc att agc gcc aaa ccc ctg 4451 Asn Glu Arg Ala Cys Ile Asp Phe Ala Ile Ser Ala Lys Pro Leu 1430 1435 1440 acg cgg tac atg ccc cag aac aag cag tcg ttc cag tac aag acg 4496 Thr Arg Tyr Met Pro Gln Asn Lys Gln Ser Phe Gln Tyr Lys Thr 1445 1450 1455 tgg acg ttc gtg gtc tca cca ccc ttt gag tat ttc atc atg gcc 4541 Trp Thr Phe Val Val Ser Pro Pro Phe Glu Tyr Phe Ile Met Ala 1460 1465 1470 atg ata gcc ctc aac aca gtg gtg ctg atg atg aag ttc tac gat 4586 Met Ile Ala Leu Asn Thr Val Val Leu Met Met Lys Phe Tyr Asp 1475 1480 1485 gcg ccc tac gag tac gaa ctg atg ttg aag tgt ctg aac atc gtg 4631 Ala Pro Tyr Glu Tyr Glu Leu Met Leu Lys Cys Leu Asn Ile Val 1490 1495 1500 ttc acg tcc atg ttc tcc atg gag tgt gtg ctc aag gtc atc gcc 4676 Phe Thr Ser Met Phe Ser Met Glu Cys Val Leu Lys Val Ile Ala 1505 1510 1515 ttt gga gtg ctg aac tat ttc aga gac gcc tgg aat gtc ttt gac 4721 Phe Gly Val Leu Asn Tyr Phe Arg Asp Ala Trp Asn Val Phe Asp 1520 1525 1530 ttt gtc act gtg ttg gga agt att act gat att tta gta aca gag 4766 Phe Val Thr Val Leu Gly Ser Ile Thr Asp Ile Leu Val Thr Glu 1535 1540 1545 att gcg aac aac ttc atc aac ctc agc ttc ctc cgc ctc ttc cgt 4811 Ile Ala Asn Asn Phe Ile Asn Leu Ser Phe Leu Arg Leu Phe Arg 1550 1555 1560 gct gcc cga ctc atc aag ctg ctc cgc caa ggc tac acc atc cgc 4856 Ala Ala Arg Leu Ile Lys Leu Leu Arg Gln Gly Tyr Thr Ile Arg 1565 1570 1575 att ctg ctc tgg acc ttc gtc cag tcc ttc aag gcc ctg ccc tat 4901 Ile Leu Leu Trp Thr Phe Val Gln Ser Phe Lys Ala Leu Pro Tyr 1580 1585 1590 gtg tgc ctg ctc atc gcc atg ctg ttc ttc atc tac gcc atc atc 4946 Val Cys Leu Leu Ile Ala Met Leu Phe Phe Ile Tyr Ala Ile Ile 1595 1600 1605 ggc atg cag gtg ttt gga aac att gct ctg gat gac gac acc agc 4991 Gly Met Gln Val Phe Gly Asn Ile Ala Leu Asp Asp Asp Thr Ser 1610 1615 1620 atc aac cgt cac aat aac ttt cgg aca ttt ctt cag gcc ttg atg 5036 Ile Asn Arg His Asn Asn Phe Arg Thr Phe Leu Gln Ala Leu Met 1625 1630 1635 ctg ctc ttc agg agt gcc acc ggg gag gcc tgg cat gag atc atg 5081 Leu Leu Phe Arg Ser Ala Thr Gly Glu Ala Trp His Glu Ile Met 1640 1645 1650 ctg tcc tgc ctc agc agt cgg gcc tgt gat gag ctc gcc aat gcc 5126 Leu Ser Cys Leu Ser Ser Arg Ala Cys Asp Glu Leu Ala Asn Ala 1655 1660 1665 acg gag tgt ggg agt gac ttc gcc tac ttc tac ttt gtc tcc ttc 5171 Thr Glu Cys Gly Ser Asp Phe Ala Tyr Phe Tyr Phe Val Ser Phe 1670 1675 1680 atc ttc ctt tgc tcc ttt ctg atg ttg aac ctc ttt gtg gct gtg 5216 Ile Phe Leu Cys Ser Phe Leu Met Leu Asn Leu Phe Val Ala Val 1685 1690 1695 atc atg gac aat ttt gag tac ctt acg cgg gac tct tcc atc cta 5261 Ile Met Asp Asn Phe Glu Tyr Leu Thr Arg Asp Ser Ser Ile Leu 1700 1705 1710 ggg cct cac cac ctg gac gaa ttc atc cgg gtc tgg gcc gag tac 5306 Gly Pro His His Leu Asp Glu Phe Ile Arg Val Trp Ala Glu Tyr 1715 1720 1725 gac ccg gct gcg tgt ggg cgc atc agt tac aat gac atg ttt gag 5351 Asp Pro Ala Ala Cys Gly Arg Ile Ser Tyr Asn Asp Met Phe Glu 1730 1735 1740 atg ctg aaa cac atg tcc ccg ccc ctg ggg ctg ggg aag aaa tgc 5396 Met Leu Lys His Met Ser Pro Pro Leu Gly Leu Gly Lys Lys Cys 1745 1750 1755 cct gct cgt gtt gcg tac aag cgc ctg gtt cgt atg aac atg ccc 5441 Pro Ala Arg Val Ala Tyr Lys Arg Leu Val Arg Met Asn Met Pro 1760 1765 1770 atc tcc aat gac gac atg acc gtc cac ttc aca tcc acg ctg atg 5486 Ile Ser Asn Asp Asp Met Thr Val His Phe Thr Ser Thr Leu Met 1775 1780 1785 gcc ctc atc cgg act gca ttg gag atc aag ctg gct cca gct ggc 5531 Ala Leu Ile Arg Thr Ala Leu Glu Ile Lys Leu Ala Pro Ala Gly 1790 1795 1800 acg aag cag cat cag tgt gac gca gag ctg agg aag gag atc tcc 5576 Thr Lys Gln His Gln Cys Asp Ala Glu Leu Arg Lys Glu Ile Ser 1805 1810 1815 tcc gtg tgg gcc aat ctg ccc cag aag acc ctg gac tta ctg gtg 5621 Ser Val Trp Ala Asn Leu Pro Gln Lys Thr Leu Asp Leu Leu Val 1820 1825 1830 cca ccc cat aaa ccc gac gag atg acg gtg ggg aag gtg tac gca 5666 Pro Pro His Lys Pro Asp Glu Met Thr Val Gly Lys Val Tyr Ala 1835 1840 1845 gct ctg atg ata ttc gac ttc tac aaa cag aac aaa acc acc aga 5711 Ala Leu Met Ile Phe Asp Phe Tyr Lys Gln Asn Lys Thr Thr Arg 1850 1855 1860 gac cag att cac caa gct cct gga ggc ctg gcc cag atg ggc ccc 5756 Asp Gln Ile His Gln Ala Pro Gly Gly Leu Ala Gln Met Gly Pro 1865 1870 1875 gtg tcc ctg ttc cac ccc ctg aag gcc acg ctg gag cag act cag 5801 Val Ser Leu Phe His Pro Leu Lys Ala Thr Leu Glu Gln Thr Gln 1880 1885 1890 ccg gct gtg ctc cga gga gcc cgc gtt ttc ctt cgg cag aag agc 5846 Pro Ala Val Leu Arg Gly Ala Arg Val Phe Leu Arg Gln Lys Ser 1895 1900 1905 tcg gcc tcc ctc agc aac ggt ggg gca gta caa acc caa gag ggc 5891 Ser Ala Ser Leu Ser Asn Gly Gly Ala Val Gln Thr Gln Glu Gly 1910 1915 1920 ggc atc aag gag tct gtc tcc tgg ggc act cag agg acc cag gag 5936 Gly Ile Lys Glu Ser Val Ser Trp Gly Thr Gln Arg Thr Gln Glu 1925 1930 1935 gtc ccc tgc gag gtg agg aca ccc ctg gag cgt ggc cac tcc aca 5981 Val Pro Cys Glu Val Arg Thr Pro Leu Glu Arg Gly His Ser Thr 1940 1945 1950 gag atc ccg gtg cag aca gga aaa ccg gct gtg gac gtc cag atg 6026 Glu Ile Pro Val Gln Thr Gly Lys Pro Ala Val Asp Val Gln Met 1955 1960 1965 cag agc atg gtc ctg aga ggc cct gac ggg gag ccc caa cct ggg 6071 Gln Ser Met Val Leu Arg Gly Pro Asp Gly Glu Pro Gln Pro Gly 1970 1975 1980 ctg gag agc cag ggc cga gca gct tcc atg ccc cgc ctg gca gca 6116 Leu Glu Ser Gln Gly Arg Ala Ala Ser Met Pro Arg Leu Ala Ala 1985 1990 1995 gag act cag cca ccc cca gat gcc agc ccc atg aag cgc tcc atc 6161 Glu Thr Gln Pro Pro Pro Asp Ala Ser Pro Met Lys Arg Ser Ile 2000 2005 2010 tcc aca ctg gca ccc cag agg ccc cac gtg gct cat ctg tgc acc 6206 Ser Thr Leu Ala Pro Gln Arg Pro His Val Ala His Leu Cys Thr 2015 2020 2025 gcg gcc ctg gac cgc gct cca gcc agc cag gcc gcc ccc ccc cac 6251 Ala Ala Leu Asp Arg Ala Pro Ala Ser Gln Ala Ala Pro Pro His 2030 2035 2040 cac cac cgc tgc cat cgc cgc agg gac cgg aag cag aag tcc ctg 6296 His His Arg Cys His Arg Arg Arg Asp Arg Lys Gln Lys Ser Leu 2045 2050 2055 gag aag ggg ccc ggc ctg tct gca gac aca gat ggc gcg ccc tac 6341 Glu Lys Gly Pro Gly Leu Ser Ala Asp Thr Asp Gly Ala Pro Tyr 2060 2065 2070 agc acc gcg ggg ccg ggc ccc ccg ccg ccc cca ggg gat ggg gca 6386 Ser Thr Ala Gly Pro Gly Pro Pro Pro Pro Pro Gly Asp Gly Ala 2075 2080 2085 gca ggc tgc cgg cgg gag cgc agg cag gag cgg ggc cgg tcc cag 6431 Ala Gly Cys Arg Arg Glu Arg Arg Gln Glu Arg Gly Arg Ser Gln 2090 2095 2100 gag cgg agg cag ccc tcc tcc tct tcc tct gag aag cag cgc ttc 6476 Glu Arg Arg Gln Pro Ser Ser Ser Ser Ser Glu Lys Gln Arg Phe 2105 2110 2115 tac tcc tgt gac cgc ttt ggg ggc cgt gag ccc ccg cag ccc aag 6521 Tyr Ser Cys Asp Arg Phe Gly Gly Arg Glu Pro Pro Gln Pro Lys 2120 2125 2130 ccc tct ctc agc agc cat ccc acg tcg ccc acg gcc ggg cag gag 6566 Pro Ser Leu Ser Ser His Pro Thr Ser Pro Thr Ala Gly Gln Glu 2135 2140 2145 cca gga ccc ccg aga cag ggt agc ggc tcc gtg aac ggg agc ccc 6611 Pro Gly Pro Pro Arg Gln Gly Ser Gly Ser Val Asn Gly Ser Pro 2150 2155 2160 ctg ctg tcg aca tct ggt gct agc acc cct ggc cgc ggc ggg cgg 6656 Leu Leu Ser Thr Ser Gly Ala Ser Thr Pro Gly Arg Gly Gly Arg 2165 2170 2175 agg cag ctc ccc cag acc ccg ctg acc ccc cgt ccc agc atc acc 6701 Arg Gln Leu Pro Gln Thr Pro Leu Thr Pro Arg Pro Ser Ile Thr 2180 2185 2190 tat aag acg gcc aac tcc tca cct gtc cac ttt gcc ggg gct cag 6746 Tyr Lys Thr Ala Asn Ser Ser Pro Val His Phe Ala Gly Ala Gln 2195 2200 2205 acc agc ctc cct gcc ttt tcc ccc ggc cgg ctt agc cgt ggc ctt 6791 Thr Ser Leu Pro Ala Phe Ser Pro Gly Arg Leu Ser Arg Gly Leu 2210 2215 2220 tcg gaa cac aac gcc ctg ctc cag aga gac ccc ctc agc cag ccg 6836 Ser Glu His Asn Ala Leu Leu Gln Arg Asp Pro Leu Ser Gln Pro 2225 2230 2235 ctg gcc ccc agc tct cgg att ggc tcc gac cct tac ctg ggg cag 6881 Leu Ala Pro Ser Ser Arg Ile Gly Ser Asp Pro Tyr Leu Gly Gln 2240 2245 2250 cgt ctg gac agt gag gct gcg gcc cgc acc cag ctt gag gac acg 6926 Arg Leu Asp Ser Glu Ala Ala Ala Arg Thr Gln Leu Glu Asp Thr 2255 2260 2265 ctc acc ttc gag gag gcc gtg gcc acc aac tcg ggc cgc tcc tcc 6971 Leu Thr Phe Glu Glu Ala Val Ala Thr Asn Ser Gly Arg Ser Ser 2270 2275 2280 cgg act tcc tac gtg tcc tcc ctg acc tcg cag tcc cac ccc ctc 7016 Arg Thr Ser Tyr Val Ser Ser Leu Thr Ser Gln Ser His Pro Leu 2285 2290 2295 cgc cgg gtg ccc aac ggc tac cac tgc act ctg ggg ctc agc tcg 7061 Arg Arg Val Pro Asn Gly Tyr His Cys Thr Leu Gly Leu Ser Ser 2300 2305 2310 ggc ggg ggc ggc cgg ggg cgg cac agc tac cac cac cct gac caa 7106 Gly Gly Gly Gly Arg Gly Arg His Ser Tyr His His Pro Asp Gln 2315 2320 2325 gac cac tgg tgc tag 7121 Asp His Trp Cys 2330 44 2331 PRT Bos taurus 44 Met Val Arg Phe Gly Asp Glu Leu Gly Gly Arg Tyr Gly Gly Pro Gly 1 5 10 15 Gly Gly Glu Arg Ala Arg Gly Gly Gly Ala Gly Val Ala Gly Gly Pro 20 25 30 Gly Pro Gly Gly Leu Gln Pro Gly Gln Arg Val Leu Tyr Lys Gln Ser 35 40 45 Ile Ala Gln Arg Ala Arg Thr Met Ala Leu Tyr Asn Pro Ile Pro Val 50 55 60 Lys Gln Asn Cys Phe Thr Val Asn Arg Ser Leu Phe Val Phe Ser Glu 65 70 75 80 Asp Asn Val Val Arg Lys Tyr Ala Lys Arg Ile Thr Glu Trp Pro Pro 85 90 95 Phe Glu Tyr Met Ile Leu Ala Thr Ile Ile Ala Asn Cys Ile Val Leu 100 105 110 Ala Leu Glu Gln His Leu Pro Asp Gly Asp Lys Thr Pro Met Ser Glu 115 120 125 Arg Leu Asp Asp Thr Glu Pro Tyr Phe Ile Gly Ile Phe Cys Phe Glu 130 135 140 Ala Gly Ile Lys Ile Ile Ala Leu Gly Phe Val Leu His Lys Gly Ser 145 150 155 160 Tyr Leu Arg Asn Gly Trp Asn Val Met Asp Phe Val Val Val Leu Thr 165 170 175 Gly Ile Leu Ala Thr Ala Gly Thr Asp Phe Asp Leu Arg Thr Leu Arg 180 185 190 Ala Val Arg Val Leu Arg Pro Leu Lys Leu Val Ser Gly Ile Pro Ser 195 200 205 Leu Gln Val Val Leu Lys Ser Ile Met Lys Ala Met Val Pro Leu Leu 210 215 220 Gln Ile Gly Leu Leu Leu Phe Phe Ala Ile Leu Met Phe Ala Ile Ile 225 230 235 240 Gly Leu Glu Phe Tyr Met Gly Lys Phe His Lys Ala Cys Phe Pro Asn 245 250 255 Ser Thr Asp Ala Asp Pro Val Gly Asp Phe Pro Cys Gly Arg Glu Ala 260 265 270 Pro Ala Arg Leu Cys Glu Gly Asp Thr Glu Cys Arg Glu Tyr Trp Ala 275 280 285 Gly Pro Asn Phe Gly Ile Thr Asn Phe Asp Asn Ile Leu Phe Ala Ile 290 295 300 Leu Thr Val Phe Gln Cys Ile Thr Met Glu Gly Trp Thr Asp Ile Leu 305 310 315 320 Tyr Asn Thr Asn Asp Ala Ala Gly Asn Thr Trp Asn Trp Leu Tyr Phe 325 330 335 Leu Pro Leu Ile Ile Ile Gly Ser Phe Phe Met Leu Asn Leu Val Leu 340 345 350 Gly Val Leu Ser Gly Glu Phe Ala Lys Glu Arg Glu Arg Val Glu Asn 355 360 365 Arg Arg Ala Phe Leu Lys Leu Arg Arg Gln Gln Gln Ile Glu Arg Glu 370 375 380 Leu Asn Gly Tyr Leu Glu Trp Ile Phe Lys Ala Glu Glu Val Met Leu 385 390 395 400 Ala Glu Glu Asp Lys Asn Ala Glu Glu Lys Ser Pro Leu Asp Val Leu 405 410 415 Lys Arg Ala Ala Thr Lys Lys Ser Arg Asn Asp Leu Ile His Ala Glu 420 425 430 Glu Gly Glu Asp Arg Phe Ala Asp Leu Cys Ala Val Gly Ser Pro Phe 435 440 445 Ala Arg Ala Ser Leu Lys Ser Gly Lys Thr Glu Ser Ser Ser Tyr Phe 450 455 460 Arg Arg Lys Glu Lys Met Phe Arg Phe Phe Ile Arg Arg Leu Val Lys 465 470 475 480 Ala Gln Ser Phe Tyr Trp Val Val Leu Cys Val Val Ala Leu Asn Thr 485 490 495 Leu Cys Val Ala Met Val His Tyr Gln Gln Pro Gln Arg Leu Thr Thr 500 505 510 Ala Leu Tyr Phe Ala Glu Phe Val Phe Leu Gly Leu Phe Leu Thr Glu 515 520 525 Met Ser Leu Lys Met Tyr Gly Leu Gly Pro Arg Ser Tyr Phe Arg Ser 530 535 540 Ser Phe Asn Cys Phe Asp Phe Gly Val Ile Val Gly Ser Ile Phe Glu 545 550 555 560 Val Val Trp Ala Ala Ile Lys Pro Gly Thr Ser Phe Gly Ile Ser Val 565 570 575 Leu Arg Ala Leu Arg Leu Leu Arg Ile Phe Lys Val Thr Lys Tyr Trp 580 585 590 Ser Ser Leu Arg Asn Leu Val Val Ser Leu Leu Asn Ser Met Lys Ser 595 600 605 Ile Ile Ser Leu Leu Phe Leu Leu Phe Leu Phe Ile Val Val Phe Ala 610 615 620 Leu Leu Gly Met Gln Leu Phe Gly Gly Gln Phe Asn Phe Gln Asp Glu 625 630 635 640 Thr Pro Thr Thr Asn Phe Asp Thr Phe Pro Ala Ala Ile Leu Thr Val 645 650 655 Phe Gln Ile Leu Thr Gly Glu Asp Trp Asn Ala Val Met Tyr His Gly 660 665 670 Ile Glu Ser Gln Gly Gly Val Ser Lys Gly Met Phe Ser Ser Val Tyr 675 680 685 Phe Ile Val Leu Thr Leu Phe Gly Asn Tyr Thr Leu Leu Asn Val Phe 690 695 700 Leu Ala Ile Ala Val Asp Asn Leu Ala Asn Ala Gln Glu Leu Thr Lys 705 710 715 720 Asp Glu Glu Glu Met Glu Glu Ala Ala Asn Gln Lys Leu Ala Leu Gln 725 730 735 Lys Ala Lys Glu Val Ala Glu Val Ser Pro Met Ser Ala Ala Asn Ile 740 745 750 Ser Ile Ala Ala Arg Gln Gln Asn Ser Ala Lys Ala Arg Ser Val Trp 755 760 765 Glu Gln Arg Ala Ser Gln Leu Arg Leu Gln Asn Leu Arg Ala Ser Cys 770 775 780 Glu Ala Leu Tyr Ser Glu Met Asp Pro Glu Glu Arg Leu Arg Phe Ala 785 790 795 800 Thr Ser Arg His Leu Arg Pro Asp Met Lys Thr His Leu Asp Arg Pro 805 810 815 Leu Val Val Glu Pro Gly Arg Asp Gly Ala Arg Gly Pro Ala Gly Gly 820 825 830 Lys Ala Arg Pro Glu Gly Gly Glu Ala Gly Glu Gly Ala Asp Pro Pro 835 840 845 Arg Arg His His Arg His Arg Asp Arg Asp Arg Asp Lys Ala Ala Ala 850 855 860 Pro Ala Gly Glu Pro Asp Arg Ala Asp Ala Pro Lys Ala Glu Gly Gly 865 870 875 880 Glu Pro Gly Ala Arg Glu Glu Arg Ala Arg Pro Arg Arg Ser Arg Ser 885 890 895 Lys Glu Ala Ala Gly Pro Arg Glu Ala Arg Ser Glu Arg Gly Arg Gly 900 905 910 Leu Gly Pro Asp Gly Gly Arg Arg His His Arg Arg Gly Ser Pro Glu 915 920 925 Glu Ala Ala Glu Arg Glu Pro Arg Arg His Arg Ala His Arg His Ala 930 935 940 Pro Glu Pro Ser Arg Glu Gly Ala Pro Gly Ser Lys Gly Glu Arg Arg 945 950 955 960 Ala Arg His Arg Gly Gly Ser Arg Ala Gly Pro Arg Glu Ala Glu Ser 965 970 975 Gly Glu Glu Pro Ser Arg Arg His Arg Ala Arg His Lys Ala Pro Pro 980 985 990 Ala His Glu Glu Ala Glu Lys Glu Ala Glu Ala Glu Asp Arg Asp Lys 995 1000 1005 Glu Pro Arg Asn His Gln Pro Arg Glu Ser His Cys Asp Leu Glu 1010 1015 1020 Ala Ser Val Val Ile Gly Val Gly Pro Val His Ala Leu Pro Ser 1025 1030 1035 Thr Cys Leu Glu Lys Val Glu Glu Gln Pro Glu Asp Ala Asp Asn 1040 1045 1050 Gln Arg Asn Val Thr Arg Met Gly Ser Gln Pro Ser Asp Leu Ser 1055 1060 1065 Thr Ala Val Arg Ile Pro Val Thr Leu Thr Gly Pro Pro Gly Glu 1070 1075 1080 Thr Thr Val Val Pro Ser Gly Asn Val Asp Leu Glu Ser Gln Ala 1085 1090 1095 Glu Gly Lys Lys Glu Val Glu Ala Asp Asp Val Met Arg Ser Gly 1100 1105 1110 Pro Arg Pro Ile Val Pro Tyr Ser Ser Met Phe Cys Leu Ser Pro 1115 1120 1125 Thr Asn Leu Leu Arg Arg Phe Cys His Tyr Ile Val Thr Met Gln 1130 1135 1140 Tyr Phe Glu Met Val Ile Leu Val Val Ile Ala Leu Ser Ser Ile 1145 1150 1155 Ala Leu Ala Ala Glu Asp Pro Val Gln Thr Asp Ser Pro Arg Asn 1160 1165 1170 Asn Val Leu Lys Tyr Met Asp Tyr Ile Phe Thr Gly Val Phe Thr 1175 1180 1185 Phe Glu Met Val Ile Lys Met Ile Asp Leu Gly Leu Leu Leu His 1190 1195 1200 Pro Gly Ala Tyr Phe Arg Asp Leu Trp Asn Ile Leu Asp Phe Ile 1205 1210 1215 Val Val Ser Gly Ala Leu Val Ala Phe Ala Phe Ser Gly Ser Lys 1220 1225 1230 Gly Lys Asp Ile Ser Thr Ile Lys Ser Leu Arg Val Leu Arg Val 1235 1240 1245 Leu Arg Pro Leu Lys Thr Ile Lys Arg Leu Pro Lys Leu Lys Ala 1250 1255 1260 Val Phe Asp Cys Val Val Asn Ser Leu Lys Asn Val Leu Asn Ile 1265 1270 1275 Leu Ile Val Tyr Met Leu Phe Met Phe Ile Phe Ala Val Ile Ala 1280 1285 1290 Val Gln Leu Phe Lys Gly Lys Phe Phe Tyr Cys Thr Asp Glu Ser 1295 1300 1305 Lys Glu Leu Glu Arg Asp Cys Arg Gly Gln Tyr Leu Asp Tyr Glu 1310 1315 1320 Lys Glu Glu Val Glu Ala Gln Pro Arg Gln Trp Lys Lys Tyr Asp 1325 1330 1335 Phe His Tyr Asp Asn Val Leu Trp Ala Leu Leu Thr Leu Phe Thr 1340 1345 1350 Val Ser Thr Gly Glu Gly Trp Pro Met Val Leu Lys His Ser Val 1355 1360 1365 Asp Ala Thr Tyr Glu Glu Gln Gly Pro Ser Pro Gly Phe Arg Met 1370 1375 1380 Glu Leu Ser Ile Phe Tyr Val Val Tyr Phe Val Val Phe Pro Phe 1385 1390 1395 Phe Phe Val Asn Ile Phe Val Ala Leu Ile Ile Ile Thr Phe Gln 1400 1405 1410 Glu Gln Gly Asp Lys Val Met Ser Glu Cys Ser Leu Glu Lys Asn 1415 1420 1425 Glu Arg Ala Cys Ile Asp Phe Ala Ile Ser Ala Lys Pro Leu Thr 1430 1435 1440 Arg Tyr Met Pro Gln Asn Lys Gln Ser Phe Gln Tyr Lys Thr Trp 1445 1450 1455 Thr Phe Val Val Ser Pro Pro Phe Glu Tyr Phe Ile Met Ala Met 1460 1465 1470 Ile Ala Leu Asn Thr Val Val Leu Met Met Lys Phe Tyr Asp Ala 1475 1480 1485 Pro Tyr Glu Tyr Glu Leu Met Leu Lys Cys Leu Asn Ile Val Phe 1490 1495 1500 Thr Ser Met Phe Ser Met Glu Cys Val Leu Lys Val Ile Ala Phe 1505 1510 1515 Gly Val Leu Asn Tyr Phe Arg Asp Ala Trp Asn Val Phe Asp Phe 1520 1525 1530 Val Thr Val Leu Gly Ser Ile Thr Asp Ile Leu Val Thr Glu Ile 1535 1540 1545 Ala Asn Asn Phe Ile Asn Leu Ser Phe Leu Arg Leu Phe Arg Ala 1550 1555 1560 Ala Arg Leu Ile Lys Leu Leu Arg Gln Gly Tyr Thr Ile Arg Ile 1565 1570 1575 Leu Leu Trp Thr Phe Val Gln Ser Phe Lys Ala Leu Pro Tyr Val 1580 1585 1590 Cys Leu Leu Ile Ala Met Leu Phe Phe Ile Tyr Ala Ile Ile Gly 1595 1600 1605 Met Gln Val Phe Gly Asn Ile Ala Leu Asp Asp Asp Thr Ser Ile 1610 1615 1620 Asn Arg His Asn Asn Phe Arg Thr Phe Leu Gln Ala Leu Met Leu 1625 1630 1635 Leu Phe Arg Ser Ala Thr Gly Glu Ala Trp His Glu Ile Met Leu 1640 1645 1650 Ser Cys Leu Ser Ser Arg Ala Cys Asp Glu Leu Ala Asn Ala Thr 1655 1660 1665 Glu Cys Gly Ser Asp Phe Ala Tyr Phe Tyr Phe Val Ser Phe Ile 1670 1675 1680 Phe Leu Cys Ser Phe Leu Met Leu Asn Leu Phe Val Ala Val Ile 1685 1690 1695 Met Asp Asn Phe Glu Tyr Leu Thr Arg Asp Ser Ser Ile Leu Gly 1700 1705 1710 Pro His His Leu Asp Glu Phe Ile Arg Val Trp Ala Glu Tyr Asp 1715 1720 1725 Pro Ala Ala Cys Gly Arg Ile Ser Tyr Asn Asp Met Phe Glu Met 1730 1735 1740 Leu Lys His Met Ser Pro Pro Leu Gly Leu Gly Lys Lys Cys Pro 1745 1750 1755 Ala Arg Val Ala Tyr Lys Arg Leu Val Arg Met Asn Met Pro Ile 1760 1765 1770 Ser Asn Asp Asp Met Thr Val His Phe Thr Ser Thr Leu Met Ala 1775 1780 1785 Leu Ile Arg Thr Ala Leu Glu Ile Lys Leu Ala Pro Ala Gly Thr 1790 1795 1800 Lys Gln His Gln Cys Asp Ala Glu Leu Arg Lys Glu Ile Ser Ser 1805 1810 1815 Val Trp Ala Asn Leu Pro Gln Lys Thr Leu Asp Leu Leu Val Pro 1820 1825 1830 Pro His Lys Pro Asp Glu Met Thr Val Gly Lys Val Tyr Ala Ala 1835 1840 1845 Leu Met Ile Phe Asp Phe Tyr Lys Gln Asn Lys Thr Thr Arg Asp 1850 1855 1860 Gln Ile His Gln Ala Pro Gly Gly Leu Ala Gln Met Gly Pro Val 1865 1870 1875 Ser Leu Phe His Pro Leu Lys Ala Thr Leu Glu Gln Thr Gln Pro 1880 1885 1890 Ala Val Leu Arg Gly Ala Arg Val Phe Leu Arg Gln Lys Ser Ser 1895 1900 1905 Ala Ser Leu Ser Asn Gly Gly Ala Val Gln Thr Gln Glu Gly Gly 1910 1915 1920 Ile Lys Glu Ser Val Ser Trp Gly Thr Gln Arg Thr Gln Glu Val 1925 1930 1935 Pro Cys Glu Val Arg Thr Pro Leu Glu Arg Gly His Ser Thr Glu 1940 1945 1950 Ile Pro Val Gln Thr Gly Lys Pro Ala Val Asp Val Gln Met Gln 1955 1960 1965 Ser Met Val Leu Arg Gly Pro Asp Gly Glu Pro Gln Pro Gly Leu 1970 1975 1980 Glu Ser Gln Gly Arg Ala Ala Ser Met Pro Arg Leu Ala Ala Glu 1985 1990 1995 Thr Gln Pro Pro Pro Asp Ala Ser Pro Met Lys Arg Ser Ile Ser 2000 2005 2010 Thr Leu Ala Pro Gln Arg Pro His Val Ala His Leu Cys Thr Ala 2015 2020 2025 Ala Leu Asp Arg Ala Pro Ala Ser Gln Ala Ala Pro Pro His His 2030 2035 2040 His Arg Cys His Arg Arg Arg Asp Arg Lys Gln Lys Ser Leu Glu 2045 2050 2055 Lys Gly Pro Gly Leu Ser Ala Asp Thr Asp Gly Ala Pro Tyr Ser 2060 2065 2070 Thr Ala Gly Pro Gly Pro Pro Pro Pro Pro Gly Asp Gly Ala Ala 2075 2080 2085 Gly Cys Arg Arg Glu Arg Arg Gln Glu Arg Gly Arg Ser Gln Glu 2090 2095 2100 Arg Arg Gln Pro Ser Ser Ser Ser Ser Glu Lys Gln Arg Phe Tyr 2105 2110 2115 Ser Cys Asp Arg Phe Gly Gly Arg Glu Pro Pro Gln Pro Lys Pro 2120 2125 2130 Ser Leu Ser Ser His Pro Thr Ser Pro Thr Ala Gly Gln Glu Pro 2135 2140 2145 Gly Pro Pro Arg Gln Gly Ser Gly Ser Val Asn Gly Ser Pro Leu 2150 2155 2160 Leu Ser Thr Ser Gly Ala Ser Thr Pro Gly Arg Gly Gly Arg Arg 2165 2170 2175 Gln Leu Pro Gln Thr Pro Leu Thr Pro Arg Pro Ser Ile Thr Tyr 2180 2185 2190 Lys Thr Ala Asn Ser Ser Pro Val His Phe Ala Gly Ala Gln Thr 2195 2200 2205 Ser Leu Pro Ala Phe Ser Pro Gly Arg Leu Ser Arg Gly Leu Ser 2210 2215 2220 Glu His Asn Ala Leu Leu Gln Arg Asp Pro Leu Ser Gln Pro Leu 2225 2230 2235 Ala Pro Ser Ser Arg Ile Gly Ser Asp Pro Tyr Leu Gly Gln Arg 2240 2245 2250 Leu Asp Ser Glu Ala Ala Ala Arg Thr Gln Leu Glu Asp Thr Leu 2255 2260 2265 Thr Phe Glu Glu Ala Val Ala Thr Asn Ser Gly Arg Ser Ser Arg 2270 2275 2280 Thr Ser Tyr Val Ser Ser Leu Thr Ser Gln Ser His Pro Leu Arg 2285 2290 2295 Arg Val Pro Asn Gly Tyr His Cys Thr Leu Gly Leu Ser Ser Gly 2300 2305 2310 Gly Gly Gly Arg Gly Arg His Ser Tyr His His Pro Asp Gln Asp 2315 2320 2325 His Trp Cys 2330 45 33 PRT Homo sapiens MISC_FEATURE (1)..(33) Amino acid sequence encoded by exon 37a; amino acid at position 1 is partly encoded by exon 36, partly by exon 37a. Identical amino acid sequence is found in Homo sapiens, Mus musculus and Rattus norvegicus 45 Cys Cys Arg Ile His Tyr Lys Asp Met Tyr Ser Leu Leu Arg Cys Ile 1 5 10 15 Ala Pro Pro Val Gly Leu Gly Lys Asn Cys Pro Arg Arg Leu Ala Tyr 20 25 30 Lys 46 32 PRT Rattus norvegicus 46 Cys Cys Arg Ile His Tyr Lys Asp Met Tyr Ser Leu Leu Arg Cys Ile 1 5 10 15 Ala Pro Pro Val Gly Leu Gly Lys Asn Cys Pro Arg Arg Leu Ala Tyr 20 25 30 47 32 PRT Rattus norvegicus 47 Cys Gly Arg Ile Ser Tyr Asn Asp Met Phe Glu Met Leu Lys His Met 1 5 10 15 Ser Pro Pro Leu Gly Leu Gly Lys Lys Cys Pro Ala Arg Val Ala Tyr 20 25 30 

What is claimed is:
 1. An isolated cell that recombinantly expresses an N-type calcium channel comprising a Ca_(V)2.2 subunit that comprises exon e37a (Ca_(V)2.2e[37a]).
 2. The isolated cell of claim 1, wherein the Ca_(V)2.2e[37a] subunit has a human sequence.
 3. The isolated cell of claim 1, wherein the Ca_(V)2.2e[37a] subunit has a mouse sequence.
 4. The isolated cell of claim 1, wherein the Ca_(V)2.2e[37a] subunit has a rat sequence. 5-6. (Canceled)
 7. An isolated neuron that expresses an N-type calcium channel comprising a Ca_(V)2.2 subunit that comprises exon e37a (Ca_(V)2.2e[37a]).
 8. The isolated neuron of claim 7, wherein the neuron further expresses a marker of nociceptive neurons.
 9. The isolated neuron of claim 8, wherein the marker of nociceptive neurons is Na_(V)1.8.
 10. The isolated neuron of claim 8, wherein the marker of nociceptive neurons is vanilloid receptor VR1.
 11. The isolated neuron of claim 8, wherein the neuron expresses both Na_(V)1.8 and vanilloid receptor VR1.
 12. A method for identifying lead compounds for a pharmacological agent useful in the treatment of disease associated with increased or decreased voltage regulated calcium influx mediated by a N-type calcium channel containing a Ca_(V)2.2e[37a] subunit comprising providing a cell or other membrane-encapsulated space comprising a Ca_(V)2.2e[37a] polypeptide; contacting the cell or other membrane-encapsulated space with a candidate pharmacological agent under conditions which, in the absence of the candidate pharmacological agent, cause a first amount of voltage regulated calcium influx into the cell or other membrane-encapsulated space; and determining a test amount of voltage regulated calcium influx as a measure of the effect of the lead compounds for a pharmacological agent on the voltage regulated calcium influx mediated by a N-type calcium channel containing a Ca_(V)2.2e[37a] subunit, wherein a test amount of voltage regulated calcium influx which is less than the first amount indicates that the candidate pharmacological agent is a lead compound for a pharmacological agent which reduces voltage regulated calcium influx and wherein a test amount of voltage regulated calcium influx which is greater than the first amount indicates that the candidate pharmacological agent is a lead compound for a pharmacological agent which increases voltage regulated calcium influx.
 13. The method of claim 12, further comprising the step of loading the cell or other membrane-encapsulated space with a calcium-sensitive compound which is detectable in the presence of calcium, wherein the calcium-sensitive compound is detected as a measure of the voltage regulated calcium influx.
 14. The method of claim 12, wherein the pharmacological agent that specifically reduces voltage regulated calcium influx mediated by a N-type calcium channel containing a Ca_(V)2.2e[37a] subunit is an agent that reduces N-type calcium channel current densities in nociceptive neurons.
 15. The method of claim 14, wherein the pharmacological agent that specifically reduces voltage regulated calcium influx mediated by a N-type calcium channel containing a Ca_(V)2.2e[37a] subunit is useful as an analgesic agent.
 16. A method for identifying compounds which selectively or preferentially bind a N-type calcium channel containing a Ca_(V)2.2e[37a] subunit comprising, providing a first cell or membrane encapsulated space which expresses a N-type calcium channel that contains a Ca_(V)2.2e[37a] subunit, providing a second cell or membrane encapsulated space which expresses a N-type calcium channel that does not contain a Ca_(V)2.2e[37a] subunit, wherein the second cell or membrane encapsulated space is identical to the first cell except for the N-type calcium channel expressed, contacting the first cell or membrane encapsulated space and the second cell or membrane encapsulated space with a compound, and determining the binding of the compound to the first cell or membrane encapsulated space and the second cell or membrane encapsulated space, wherein a compound which binds the first cell or membrane encapsulated space but does not bind the second cell or membrane encapsulated space is a compound which selectively binds the N-type calcium channel that contains a Ca_(V)2.2e[37a] subunit, and wherein a compound which binds the first cell or membrane encapsulated space in an amount greater than the compound binds the second cell or membrane encapsulated space is a compound which preferentially binds the N-type calcium channel that contains a Ca_(V)2.2e[37a] subunit.
 17. The method of claim 16, wherein the N-type calcium channel that does not contain a Ca_(V)2.2e[37a] subunit is a N-type calcium channel that contains a Ca_(V)2.2e[37b] subunit.
 18. A method for identifying compounds which selectively or preferentially bind to a Ca_(V)2.2e[37a] isoform comprising, providing a Ca_(V)2.2e[37a] isoform polypeptide or nucleic acid, providing a Ca_(V)2.2e[37b] isoform polypeptide or nucleic acid, contacting the Ca_(V)2.2e[37a] isoform polypeptide or nucleic acid and the Ca_(V)2.2e[37b] subunit isoform polypeptide or nucleic acid with a compound, and determining the binding of the compound to the Ca_(V)2.2e[37a] isoform polypeptide or nucleic acid and the Ca_(V)2.2e[37b] isoform polypeptide or nucleic acid, wherein a compound which binds the Ca_(V)2.2e[37a] isoform polypeptide or nucleic acid but does not bind the human N-type calcium channel Ca_(V)2.2e[37b] isoform polypeptide or nucleic acid is a compound which selectively binds the Ca_(V)2.2e[37a] isoform, and wherein a compound which binds the Ca_(V)2.2e[37a] isoform polypeptide or nucleic acid in an amount greater than the compound binds the Ca_(V)2.2e[37b] isoform polypeptide or nucleic acid is a compound which preferentially binds the Ca_(V)2.2e[37a] isoform. 19-23. (Canceled)
 24. A method for preparing an analgesic agent, comprising identifying an agent that selectively or preferentially reduces calcium channel current densities in nociceptive neurons mediated by N-type calcium channels containing a Ca_(V)2.2e[37a] subunit, and formulating the agent for administration to a subject in need of such treatment.
 25. (Canceled)
 26. A double stranded RNA molecule specific for Ca_(V)2.2e[37a] RNA.
 27. The double stranded RNA molecule of claim 26, wherein the molecule is 21-23 nucleotides in length.
 28. The double stranded RNA molecule of claim 26, wherein the molecule has a 3′ overhang.
 29. The double stranded RNA molecule of claim 28, wherein the 3′ overhang is 2 nucleotides in length.
 30. The double stranded RNA molecule of claim 26, wherein the molecule is a single molecule that comprises a hairpin structure.
 31. A method for inhibiting calcium influx in a neuronal cell mediated by a N-type calcium channel containing a Ca_(V)2.2e[37a] subunit comprising contacting the neuronal cell with an amount of a Ca_(V)2.2e[37a] inhibitor effective to inhibit calcium influx in the mammalian cell.
 32. The method of claim 31, wherein the inhibitor is selected from the group consisting of an antibody which selectively binds the Ca_(V)2.2e[37a] polypeptide, an antisense nucleic acid that reduces expression of a Ca_(V)2.2e[37a] polypeptide, a siRNA that reduces expression of a Ca_(V)2.2e[37a] polypeptide.
 33. A method for treating a subject afflicted by pain mediated by a N-type calcium channel containing a Ca_(V)2.2e[37a] subunit comprising administering to a subject in need of such treatment an inhibitor of the Ca_(V)2.2e[37a] polypeptide in an amount effective to inhibit voltage regulated calcium influx and thereby to reduce the pain.
 34. The method of claim 33, wherein the inhibitor is selected from the group consisting of an antibody which selectively binds the Ca_(V)2.2e[37a] polypeptide, an antisense nucleic acid that reduces expression of a Ca_(V)2.2e[37a] polypeptide, a siRNA that reduces expression of a Ca_(V)2.2e[37a] polypeptide.
 35. The method of claim 33, wherein the inhibitor is administered prophylactically to a subject at risk of being afflicted with pain.
 36. The method of claim 33, wherein the pain is neuropathic pain. 